Extended release injectable formulations comprising an isoxazoline active agent, methods and uses thereof

ABSTRACT

This invention relates to extended release injectable formulations for combating parasites in animals, comprising at least one isoxazoline active agent, a pharmaceutically acceptable polymer, and a solvent. This invention also provides for improved methods for eradicating, controlling, and preventing parasite infections and infestations in an animal comprising administering the extended release injectable formulations of the invention to the animal in need thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/144,871 filed on Apr. 8, 2015, which is herein incorporated byreference.

FIELD OF THE INVENTION

The present invention provides extended release injectable formulationscomprising at least one isoxazoline active agent, a pharmaceuticallyacceptable polymer and a solvent; the use of these formulations againstparasites (including ectoparasites (e.g., fleas or ticks) and/orendoparasites), and methods for preventing or treating parasiticinfections and infestations in animals.

BACKGROUND OF THE INVENTION

Animals such as mammals and birds are often susceptible to parasiteinfestations/infections. These parasites may be ectoparasites, such asfleas, ticks and parasitic flies, and endoparasites such as nematodesand other worms. Domesticated animals, such as cats and dogs, are ofteninfested with one or more of the following ectoparasites:

-   -   fleas (e.g. Ctenocephalides spp., such as Ctenocephalides felis        and the like);    -   ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp.,        Amblyomma spp., and the like);    -   mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., and        the like);    -   lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus        spp. and the like);    -   mosquitoes (Aedes spp., Culex spp., Anopheles spp. and the        like); and    -   flies (Haematobia spp., Musca spp., Stomoxys spp., Dermatobia        spp., Cochliomyia spp. and the like).

Fleas are a particular problem because not only do they adversely affectthe health of the animal or human, but they also cause a great deal ofpsychological stress. Moreover, fleas may also transmit pathogenicagents to animals and humans, such as tapeworm (Dipylidium caninum).

Similarly, ticks are also harmful to the physical and psychologicalhealth of the animal or human. However, the most serious problemassociated with ticks is that they are vectors of pathogenic agents inboth humans and animals. Major diseases which may be transmitted byticks include borreliosis (Lyme disease caused by Borrelia burgdorferi),babesiosis (or piroplasmosis caused by Babesia spp.) and rickettsioses(e.g. Rocky Mountain spotted fever). Ticks also release toxins whichcause inflammation or paralysis in the host. Occasionally, these toxinsare fatal to the host.

Likewise, farm animals are also susceptible to parasite infestations.For example, cattle are affected by a large number of parasites. Aparasite which is prevalent among cattle in some regions are ticks ofthe genus Rhipicephalus, especially those of the species microplus(cattle tick), decoloratus and annulatus. Ticks such as Rhipicephalusmicroplus (formerly Boophilus microplus) are difficult to controlbecause they lay eggs in the pasture where farm animals graze. Thisspecies of ticks is considered a one-host tick and spends immature andadult stages on one animal before the female engorges and falls off thehost to lay eggs in the environment. The life cycle of the tick isapproximately three to four weeks. In addition to cattle, Rhipicephalusmicroplus may infest buffalo, horses, donkeys, goats, sheep, deer, pigs,and dogs. A heavy tick burden on animals can decrease production anddamage hides as well as transmit diseases such as babesiosis (“cattlefever”) and anaplasmosis.

Animals and humans also suffer from endoparasitic infections including,for example, helminthiasis, which is caused by of parasitic wormscategorized as cestodes (tapeworm), nematodes (roundworm) and trematodes(flatworm or flukes). These parasites adversely affect the nutrition ofthe animal and cause severe economic losses in pigs, sheep, horses, andcattle as well as affecting companion animals and poultry. Otherparasites which occur in the gastrointestinal tract of animals andhumans include those from the genus Ancylostoma, Necator, Ascaris,Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichuris,Enterobius and parasites which are found in the blood or other tissuesand organs such as filarial worms and the extra intestinal stages ofStrongyloides, Toxocara and Trichinella.

Recently, isoxazole and isoxazoline-containing compounds have beendemonstrated to be effective against parasites that harm animals. Forexample, U.S. Pat. No. 7,964,204 (to DuPont, incorporated by referenceherein in its entirety) discloses isoxazoline compounds according toFormula (I) below, which are active against ectoparasites and/orendoparasites.

In addition, published patent application nos. US 2010/0254960 A1, WO2007/070606 A2, WO 2007/123855 A2, WO 2010/003923 A1, U.S. Pat. No.7,951,828 & U.S. Pat. No. 7,662,972, US 2010/0137372 A1, US 2010/0179194A2, US 2011/0086886 A2, US 2011/0059988 A1, US 2010/0179195 A1 and WO2007/075459 A2 and U.S. Pat. Nos. 7,951,828 and 7,662,972 describevarious other parasiticidal isoxazoline compounds. Other publishedpatent applications that describe various other parasiticidalisoxazoline compounds and formulations comprising the same include WO2007/079162 A1, WO 2008/154528 A1, WO 2009/002809 A2, WO 2011/149749 A1,WO 2014/439475 A1, U.S. Pat. No. 8,466,115, WO 2012/120399, WO2014/039484, WO 2014/189837, (Zoetis) and WO2012 120135A1 (Novartis). WO2012/089623 describes topical localized isoxazoline formulationscomprising glycofurol. WO 2013/039948 A1 provides for topical veterinarycompositions comprising at least one isoxazoline active agent and WO2013/119442 A1 provides for oral veterinary compositions such as a softchew, which comprise at least one isoxazoline active agent.

In addition to topical and oral dosage forms, it is sometimes possibleto formulate active agents as extended release injectable formulations,depending upon, for example, the physiochemical properties of theindividual active agent. These properties include, for example,solubility, bioavailability, etc. In some cases it may be possible toformulate active agents in extended release formulations comprising apharmaceutically acceptable polymer that controls the release of theactive agent in the animal's body from the formulation over an extendedperiod of time. The meaning of “extended release” formulations in theveterinary medicine field is the subject of the article “TerminologyChallenges: Defining Modified Release Dosage Forms in VeterinaryMedicine” by Marilyn N. Martinez, Danielle Lindquist and Sanja Modric(Journal of Pharmaceutical Sciences, vol. 99, no. 8, August 2010). Thedefinition for an “extended release” dosage form proposed in the article“Dosage forms that are formulated in such a manner as to make thecontained medicament available over an extended period of time” isconsistent with the use of this term in the present application in whichthe formulation components induce the release characteristics of theactive ingredient rather than the intrinsic properties of the activeitself being responsible for the long acting nature of the formulation.For example, U.S. Pat. No. 6,733,767 and U.S. Pat. No. 8,362,086 providefor long acting injectable formulations comprising a bioactivesubstance, such as, for example, an avermectin or a milbemycin and abiologically acceptable polymer. U.S. Pat. No. 5,330,768 provides fordegradable polymeric matrices for the delivery of drugs by blendingpolymers that degrade by hydrolysis (e.g., poly(L-lactic acid), nonionicsurfactants and block copolymers of polyethylene oxide and polypropyleneoxide.

Fluorinated compounds, such as the some of the isoxazoline compoundsprovided for in the inventive formulations, often present additionalchallenges as compared to their non-fluorinated counterparts whenformulating the compounds in extended release injectable formulationsbecause the presence of fluorine groups make it more difficult toachieve the desired release properties of the compound from thepolymeric matrices, which form the depot. Fluorinated organic compoundsare very hydrophobic. In part, this is due to the low surface energieswhich make the compound less wettable. See, N. L. Jarvis and W. A.Zisman, “Surface Chemistry of Fluorochemicals”, U.S. Naval ResearchLaboratory, Washington, D.C. (1965). This property hinders the hydrationof polymers such as poly(L-lactic acid), thereby delaying thedegradation of the polymer and delaying the release of the fluorinatedcompound from the depot.

Notwithstanding the compositions comprising isoxazoline active agentsalone or in combination with other active agents described in thedocuments above, there is a need for veterinary compositions and methodswith improved duration of efficacy, and/or bioavailability, and/orspectrum of coverage to protect animals against endoparasites and/orectoparasites. More specifically, there is a need to develop a longeracting injectable formulation comprising an isoxazoline compound, whichhas good bioavailability and provides a high level of efficacy againstectoparasites (e.g., fleas and ticks) for a long duration (e.g., fromthree (3) up to twelve (12) months, while exhibiting reduced injectionsite irritation on the animal.

INCORPORATION BY REFERENCE

Any foregoing applications, and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

SUMMARY OF THE INVENTION

The present invention provides novel and inventive extended releaseinjectable formulations for the treatment or prevention of parasiteinfections or infestations in an animal comprising an antiparasiticeffective amount of at least one isoxazoline active agent, apharmaceutically acceptable polymer and, optionally, a solvent. In anembodiment, the extended release injectable formulations of theinvention comprise an antiparasitic effective amount of at least oneisoxazoline active agent, a pharmaceutically acceptable biodegradablepolymer, and a solvent. As used herein, the term “poloxamer” means ablock copolymer of ethylene oxide and propylene oxide. For the purposeof the present application poloxamers that are not co-polymerized withother pharmaceutically acceptable polymers are considered solvents orsurfactants rather than a pharmaceutically acceptable polymer. Differentgrades, sources, and brands of block copolymers of ethylene oxide andpropylene oxide may be used in the extended release injectableformulations of the invention. Likewise, for the purposes of thisapplication, liquid polyethylene glycols (PEGs) that are notco-polymerized with other pharmaceutically acceptable polymers areconsidered to be a solvent and are not considered to be apharmaceutically acceptable polymer

In accordance with this invention, it has been discovered that theinventive extended release injectable formulations generally showdesirable bioavailability and duration of efficacy. Further, theinventive extended release formulations generally do not showundesirable irritation on the injection site of the animal. Thecompositions also provide desirable safety profiles toward thewarm-blooded and avian animal recipients. In addition, it has beendiscovered that a single administration of such formulations generallyprovides potent activity against one or more parasites (e.g.,ectoparasites), while also tending to provide fast onset of activity,long duration of activity, and/or desirable safety and release profiles.

The invention encompasses uses or veterinary uses of the isoxazolinecompositions for the treatment or prevention or prophylaxis of parasiticinfections and infestations of animals (either wild or domesticated),including livestock and companion animals such as cats, dogs, horses,chickens, sheep, goats, pigs, turkeys and cattle, with the aim ofridding these hosts of parasites commonly encountered by such animals.

The invention also provides methods for the treatment or prevention ofparasitic infections and infestations in animals, comprisingadministering an effective amount of extended release injectableformulations comprising an antiparasitic effective amount of at leastone isoxazoline compound together with a pharmaceutically acceptablepolymer and a solvent. Surprisingly, it has been found that theinventive isoxazoline-containing extended release injectableformulations described herein exhibit superior broad spectrum efficacyagainst harmful parasites (e.g. ectoparasites such as fleas and ticks)more rapidly, and over a long duration compared to other injectableformulations containing isoxazoline active agents known in the art whileexhibiting acceptable irritation injection site characteristics.

This invention also provides for the use of an isoxazoline in thepreparation of extended release injectable formulations for thetreatment or prevention of an animal against parasites.

In one embodiment, the invention provides for extended releaseinjectable formulations comprising antiparasitic effective amounts of atleast one isoxazoline of formula (I) below, in combination and apharmaceutically or veterinary acceptable polymer and a solvent, wherevariables B¹, B², B³, R¹, Y and Q are defined herein and the asterisksignifies that the carbon is a quaternary carbon.

In other embodiments, the extended release injectable formulations ofthe invention comprise effective amounts of at least one isoxazolineactive agent of formulae

wherein variables A¹, A², A³, A⁴, A⁵, A⁶, B¹, B², B³, R¹, R², R³, R⁴,R⁵, W, n, X¹, X², X³, R₁, X, A₁, A₂, G, Y, T, R^(3a) and R^(3b) for eachformula are defined herein.

In some embodiments, the extended release injectable formulations andmethods comprise 4-[5-[3-chloro-5-(trifluorom ethyl)phenyl]-4,5-di hydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalenecarboxamide (compound of Formula IIc) as the active agent. These compoundsare described in U.S. Pat. Nos. 7,964,204 B2 and 8,410,153 B2, bothincorporated herein by reference in their entirety.

In other embodiments, the extended release injectable formulations mayfurther comprise one or more additional active agents that aresystemically active. Systemically-acting active agents include, but arenot limited to, isoxazoline active agents of different structure, asystemically-acting neonicotinoid active agent, a systemically-acting1-N-arylpyrazole active agent, macrocyclic lactones such as avermectinand milbemycin compounds, a cyclic depsipeptide such as emodepside orPF1022A, or analogs thereof, benzimidazoles, imidazothiazoles, atetrahydropyrimidine active agent, an organophosphate active agent,levamisole, a paraherquamide active agent and/or a marcfortine activeagent, praziquantel, closantel, clorsulon, pyrantel, a spinosyn orspinosoid active agent, an amino acetonitrile active agent, anaryloazol-2-yl cyanoethyl active agent and a systemically-acting insectgrowth regulator. In one embodiment, the extended release injectableformulations comprise at least one macrocyclic lactone active agent,including, but not limited to, avermectins or milbemycins. In someembodiments, the avermectin or milbemycin active agent is eprinomectin,ivermectin, abamectin, selamectin, doramectin, milbemectin, milbemycinD, milbemycin oxime, or moxidectin.

In other embodiments, the compositions and methods comprise at least oneof thiabendazole, oxibendazole, mebendazole, fenbendazole, oxfendazole,albendazole, triclabendazole, febantel, levamisole, pyrantel, morantel,praziquantel, closantel, clorsulon, an amino acetonitrile active agent,or an aryloazol-2-yl cyanoethylamino active agent.

In yet another embodiment, the compositions and methods comprise atleast cyclic depsipeptide active agent including, but not limited to,emodepside and PF1022A, or analogs thereof.

It is an object of the invention to not encompass within the inventionany previously known product, process of making the product, or methodof using the product such that the Applicants reserve the right andhereby disclose a disclaimer of any previously known product, process,or method. It is further noted that the invention does not intend toencompass within the scope of the invention any product, process, ormaking of the product or method of using the product, which does notmeet the written description and enablement requirements of the USPTO(35 U.S.C. §112, first paragraph) or the EPO (Article 83 of the EPC),such that Applicants reserve the right and hereby disclose a disclaimerof any previously described product, process of making the product, ormethod of using the product.

These and other embodiments are disclosed or are obvious from andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION

The present invention provides for novel and inventive extended releaseinjectable formulations treatment or prevention of parasite infectionsor infestations in an animal comprising an antiparasitic effectiveamount of at least one isoxazoline compound, a pharmaceuticallyacceptable polymer and optionally a solvent or mixture of solvents.

Also provided are methods and uses for the treatment and/or prophylaxisof parasitic infections and infestations of animals, comprisingadministering to an animal in need thereof an extended releaseformulation comprising an antiparasitic effective amount of at least oneisoxazoline compound, a pharmaceutically acceptable polymer andoptionally a solvent or mixture of solven.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising anantiparasitic effective amount of at least one isoxazoline compound andan effective amount of at least one additional systemically-actingactive agent, a pharmaceutically acceptable polymer and, optionally, asolvent or mixture of solvent.

In a preferred embodiment of the invention, the pharmaceuticallyacceptable polymer is a pharmaceutically acceptable biodegradablepolymer.

In one embodiment, the present invention provides for an extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, which is:

-   -   i) an isoxazoline compound of formula (I):

wherein:

-   -   B¹, B² and B³ are each independently C—R or N;    -   each R is independently H, halogen, cyano, —NO₂, alkyl,        haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkyl        sulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkyl sulfonyl,        alkylamino, dialkylamino or alkoxycarbonyl;    -   R¹ is C₁-C₃alkyl or C₁-C₃haloalkyl;    -   Y is an optionally substituted phenylene, naphthylene,        indanylene, a 5- or 6-membered heteroarylene or an 8-10-membered        fused heterobicyclylene, wherein the optional substituents are        selected from the group consisting of halogen, alkyl, haloalkyl,        cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio,        haloalkylthio, alkyl sulfinyl, haloalkyl sulfinyl,        alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, —CN        or —NO₂ and NH₂—C(═S)—;    -   Q is X—NR²R³, the group (—CH₂—)(—CH₂—)N—R³, OH, NH₂, alkoxy,        haloalkoxy, alkylamino, haloalkylamino, dialkylamino,        halodialkylamino, thiol, alkylthio, haloalkylthio,        alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,        haloalkylsulfonyl, or an optionally substituted 5- or 6-membered        carbocyclyl, heterocyclyl or heteroaryl ring;    -   X is (CH₂), CH(CH₃), CH(CN), C(═O) or C(═S);    -   R² is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl,        cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;    -   R³ is H, OR⁷, NR⁸R⁹ or Q¹; or alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl,        cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,        alkylaminocarbonyl or dialkylaminocarbonyl, each optionally        substituted with one or more substituents independently selected        from R⁴; or    -   R² and R³ are taken together with the nitrogen to which they are        attached to form a ring containing 2 to 6 atoms of carbon and        optionally one additional atom selected from the group        consisting of N, S and O, said ring optionally substituted with        1 to 4 substituents independently selected from the group        consisting of alkyl, halogen, —CN, —NO₂ and alkoxy;    -   each R⁴ is independently halogen; alkyl, cycloalkyl, alkoxy,        alkylthio, haloalkylthio, alkylsulfinyl, haloalkyl sulfinyl,        alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino,        dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl,        alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,        haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl,        dihaloalkylaminocarbonyl, hydroxy, —NH₂, —CN or —NO₂; or Q²;    -   each R⁵ is independently halogen, alkoxy, haloalkoxy, alkylthio,        haloalkylthio, alkylsulfinyl, haloalkyl sulfinyl, alkylsulfonyl,        haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, —CN        or —NO₂;    -   each R⁶ is independently halogen, alkyl, haloalkyl, cycloalkyl,        halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio,        alkyl sulfinyl, haloalkylsulfinyl, alkyl sulfonyl,        haloalkylsulfonyl, alkylamino, dialkylamino, —CN, —NO₂, phenyl        or pyridinyl;    -   R⁷ is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl        or cycloalkylalkyl, each optionally substituted with one of more        halogen;    -   R⁸ is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl,        cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;    -   R⁹ is H; Q³; or alkyl, alkenyl, alkynyl, cycloalkyl,        alkylcycloalkyl or cycloalkylalkyl, each optionally substituted        with one or more substituents independently selected from R⁴; or    -   R⁸ and R⁹ are taken together with the nitrogen to which they are        attached to form a ring containing 2 to 6 atoms of carbon and        optionally one additional atom selected from the group        consisting of N, S and O, said ring optionally substituted with        1 to 4 substituents independently selected from the group        consisting of alkyl, halogen, —CN, —NO₂ and alkoxy;    -   Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an        8-, 9- or 10-membered fused bicyclic ring system optionally        containing one to three heteroatoms selected from up to 1 O, up        to 1 S and up to 3 N, each ring or ring system optionally        substituted with one or more substituents independently selected        from R⁵;    -   Q² is independently a phenyl ring or a 5- or 6-membered        heterocyclic ring, each ring optionally substituted with one or        more substituents independently selected from R⁶;    -   Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring,        each ring optionally substituted with one or more substituents        independently selected from R⁶; and    -   n is 0, 1 or 2;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In one embodiment of the invention directed to extended releasecompositions comprising an isoxazoline compound of formula (I), Y isselected from Y-1, Y-2, Y-3, Y-4 where Z is nitrogen or CH, Y-5 or Y-6shown below:

In one embodiment of the invention comprising an isoxazoline compound offormula (I), the group Q is X—NR²R³. In another embodiment, Q is X—NR²R³wherein R² is H or C₁-C₃alkyl and R³ is C₁-C₃alkyl optionallysubstituted by R⁴. In yet another embodiment, Q is X—NR²R³ wherein R² isH and R³ is C₁-C₃alkyl optionally substituted by alkylthio,haloalkylthio, alkyl sulfinyl, haloalkylsulfinyl, alkyl sulfonyl,haloalkyl sulfonyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, haloalkyl carbonyl, haloalkoxycarbonyl,haloalkylaminocarbonyl or dihaloalkylaminocarbonyl. In anotherembodiment, Q is X—NR²R³ wherein R² is H and R³ is C₁-C₃alkyl optionallysubstituted by alkylthio, haloalkylthio, alkylaminocarbonyl,dialkylaminocarbonyl, haloalkylaminocarbonyl ordihaloalkylaminocarbonyl. In still another embodiment, Q is—C(O)NHCH₂C(O)NHCH₂CF₃. In yet another embodiment, Q is—C(O)CH₂S(O)₂CH₃. In another embodiment, Q is —C(O)NHCH₂CH₂SCH₃. Inanother embodiment, Q is the group (—CH₂—)(CH₂—)N(CO)CH₂S(O)₂CH₃.

In another embodiment, the present invention provides for an extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, which is:

-   -   i) an isoxazoline compound of formula (I):

wherein:

A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from the groupconsisting of CR³ and N, provided that at most 3 of A¹, A², A³, A⁴, A⁵and A⁶ are N;

B¹, B² and B³ are independently selected from the group consisting ofCR² and N;

W is O or S;

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₄-C₇alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionallysubstituted with one or more substituents independently selected fromR⁶;

each R² is independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆haloalkylthio,C₁-C₆alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl,C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂;

each R³ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆haloalkylthio, C₁-C₆ alkylsulfinyl,C₁-C₆haloalkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆haloalkylsulfonyl,C₁-C₆ alkylamino, C₂-C₆ dialkylamino, —CN or —NO₂;

R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇cycloalkylalkyl, C₂-C₇alkylcarbonyl orC₂-C₇alkoxycarbonyl;

R⁵ is H, OR¹⁰, NR¹¹R¹² or Q¹; or C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl orC₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁷; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂alkoxy;

each R⁶ is independently halogen, C₁-C₆ alkyl, C₁-C₆alkoxy,C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, —CN or —NO₂;

each R⁷ is independently halogen; C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl,C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino,C₂-C₇alkylcarbonyl, C₂-C₇alkoxycarbonyl, C₂-C₇alkylaminocarbonyl, C₃-C₉dialkylaminocarbonyl, C₂-C₇haloalkylcarbonyl, C₂-C₇haloalkoxycarbonyl,C₂-C₇ haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl, hydroxy,—NH₂, —CN or —NO₂; or Q²;

each R⁸ is independently halogen, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl,C₁-C₆haloalkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ haloalkylsulfonyl,C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂;

each R⁹ is independently halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆haloalkylthio, C₁-C₆ alkylsulfinyl,C₁-C₆haloalkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆haloalkylsulfonyl,C₁-C₆ alkylamino, C₂-C₆ dialkylamino, —CN, —NO₂, phenyl or pyridinyl;

R¹⁰ is H; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionallysubstituted with one of more halogen;

R¹¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇cycloalkylalkyl, C₂-C₇alkylcarbonyl orC₂-C₇alkoxycarbonyl;

R¹² is H; Q³; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, eachoptionally substituted with one or more substituents independentlyselected from R⁷; or

R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂ alkoxy; is a phenyl ring, a 5- or 6-membered heterocyclicring, or an 8-, 9- or 10-membered fused bicyclic ring system optionallycontaining one to three heteroatoms selected from up to 1 O, up to 1 Sand up to 3 N, each ring or ring system optionally substituted with oneor more substituents independently selected from R⁸;

each Q² is independently a phenyl ring or a 5- or 6-memberedheterocyclic ring, each ring optionally substituted with one or moresubstituents independently selected from R⁹;

Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ringoptionally substituted with one or more substituents independentlyselected from R⁹; and

n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

ii) an isoxazoline compound of formula (III):

wherein:

R₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachwhich is unsubstituted or substituted with one or more of halogen,hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—,R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

X is aryl or heteroaryl, which may be unsubstituted or substituted byone or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

A₁ is oxygen; and

A₂ is oxygen, NR₂ or CR₇R₈;

G is G-1 or G-2;

B₁, B₂, B₃, B₄ and B₅ are independently N or C—R₉;

Y is hydrogen, halogen, —CN; or Y is alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl,cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which isunsubstituted or substituted with one or more of halogen, hydroxy,amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—,R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6,Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;

R₂, R₃ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyakyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, R₁₀S(O)—, R₁₀S(O)₂—, R₁₀C(O)—, R₁₀C(S)—,R₁₀R₁₁NC(O)—, R₁₀R₁₁NC(S)—R₁₀OC(O)—;

R₄, R₅ and R₆ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyakyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, aryl or heteroaryl;

R₇ and R₈ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyakyl, alkenyl, haloalkenyl, alkynylor haloalkynyl;

R₉ is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each which is unsubstituted or substituted with one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

R₁₀, R₁₁, R₁₂ and R₁₃ are each independently hydrogen, alkyl, haloalkyl,thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,haloalkenyl, alkynyl or haloalkynyl; or

R₁₀ together with R₁₁ form ═O, ═S or ═NR₂; or

R₁₂ together with R₁₃ form ═O, ═S or ═NR₂;

W is O, S or NR₂;

n is 1-4; and

m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

-   -   iii) an isoxazoline compound of formula (IV)

wherein X¹, X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof; and/or

-   -   iv) an isoxazoline compound of formula (V)

wherein X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof; and/or

-   -   v) an isoxazoline compound of formula (VI):

wherein R¹, R² and R³ are independently H, Cl, F or CF₃;

Y is the diradical group

and

T is a C₁-C₆-alkyl group which is unsubstituted or substituted byhalogen, cyano, nitro, amino, hydroxyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-alkylthio, carboxy, carbamoyl or C₂-C₆-alkanoylgroup which may be unsubstituted or substituted in the alkyl portion byhalogen or a pharmaceutical acceptable salt thereof; and/or

-   -   vi) an isoxazoline compound of formula (VII):

wherein Y is hydrogen, fluoro, chloro or bromo;

R¹ is phenyl substituted with 2-4 substituents selected from halogen,methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy ortrifluoroethoxy;

R² is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;

R^(3a) and R^(3b) are independently selected from hydrogen, methyl,ethyl or fluoromethyl; or R^(a) and R^(3b) together combine with thecarbon to which they are attached to form a cyclopentyl ring or acyclohexyl ring; or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

The compound of formula (III) is disclosed in U.S. Pat. No. 7,662,972and in published U.S. Patent Application No. US 2011/0059988 A1, bothincorporated herein by reference. The compound of formula (IV) isdisclosed in U.S. Pat. No. 8,466,115 B2, which is incorporated herein byreference. The compound of formula (VI) is described in U.S. Pat. No.8,383,659, which is also incorporated herein by reference. The compoundof formula (VII) is described in U.S. Pat. No. 8,853,186 B2, which isincorporated herein by reference.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (II):

wherein:

A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from the groupconsisting of CR³ and N, provided that at most 3 of A¹, A², A³, A⁴, A⁵and A⁶ are N;

B¹, B² and B³ are independently selected from the group consisting ofCR² and N;

W is O or S;

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₄-C₇alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionallysubstituted with one or more substituents independently selected fromR⁶;

each R² is independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl,C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂;

each R³ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆haloalkylthio, C₁-C₆ alkylsulfinyl,C₁-C₆haloalkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆haloalkylsulfonyl,C₁-C₆ alkylamino, C₂-C₆ dialkylamino, —CN or —NO₂;

R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇cycloalkylalkyl, C₂-C₇alkylcarbonyl orC₂-C₇alkoxycarbonyl;

R⁵ is H, OR¹⁰, NR¹¹R¹² or Q¹; or C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇alkylcycloalkyl orC₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁷; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂alkoxy; each R⁶ is independently halogen, C₁-C₆ alkyl,C₁-C₆alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl,—CN or —NO₂;

each R⁷ is independently halogen; C₁-C₆ alkyl, C₃-C₆cycloalkyl,C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl,C₁-C₆ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino,C₂-C₇alkylcarbonyl, C₂-C₇alkoxycarbonyl, C₂-C₇alkylaminocarbonyl, C₃-C₉dialkylaminocarbonyl, C₂-C₇haloalkylcarbonyl, C₂-C₇haloalkoxycarbonyl,C₂-C₇ haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl, hydroxy,—NH₂, —CN or —NO₂; or Q₂;

each R⁸ is independently halogen, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl,C₁-C₆haloalkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆ haloalkylsulfonyl,C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂;

each R⁹ is independently halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl,C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylthio, C₁-C₆haloalkylthio, C₁-C₆ alkylsulfinyl,C₁-C₆haloalkylsulfinyl, C₁-C₆alkylsulfonyl, C₁-C₆haloalkylsulfonyl,C₁-C₆ alkylamino, C₂-C₆ dialkylamino, —CN, —NO₂, phenyl or pyridinyl;

R¹⁰ is H; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionallysubstituted with one of more halogen;

R¹¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇cycloalkylalkyl, C₂-C₇alkylcarbonyl orC₂-C₇alkoxycarbonyl;

R¹² is H; Q³; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, eachoptionally substituted with one or more substituents independentlyselected from R⁷; or

R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂alkoxy;

Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-or 10-membered fused bicyclic ring system optionally containing one tothree heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, eachring or ring system optionally substituted with one or more substituentsindependently selected from R⁸;

each Q² is independently a phenyl ring or a 5- or 6-memberedheterocyclic ring, each ring optionally substituted with one or moresubstituents independently selected from R⁹;

Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ringoptionally substituted with one or more substituents independentlyselected from R⁹; and

n is 0, 1 or 2

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (IIa):

or a pharmaceutically acceptable salt thereof

wherein

R² independently is halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl

R⁴ is H or C₁-C₆ alkyl;

R⁵ is C₁-C₄ alkyl optionally substituted with one or more R⁷; and R⁷ isC₂-C₇ alkylcarbonyl, C₂-C₇alkoxycarbonyl, C₂-C₇alkylaminocarbonyl, C₃-C₉dialkylaminocarbonyl, C₂-C₇haloalkylcarbonyl, C₂-C₇haloalkoxycarbonyl,C₂-C₇haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl (e.g.,—CH₂C(O)NHCH₂CF₃); and

n is 0, 1 or 2

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for an extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) an antiparasitic effective amount of an isoxazoline active agent offormula (IIb)

wherein X² and X³ are each independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalyl

-   -   or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (IIc):

-   -   or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (IId):

-   -   or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (IIe):

-   -   or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (IIi):

-   -   or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (III):

wherein:

R₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachwhich is unsubstituted or substituted with one or more of halogen,hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—,R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

X is aryl or heteroaryl, which may be unsubstituted or substituted byone or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

A₁ is oxygen; and

A₂ is oxygen, NR₂ or CR₇R₈;

G is G-1 or G-2;

B₁, B₂, B₃, B₄ and B₅ are independently N or C—R₉;

Y is hydrogen, halogen, —CN; or Y is alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl,cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which isunsubstituted or substituted with one or more of halogen, hydroxy,amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—,R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6,Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;

R₂, R₃ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, R₁₀S(O)—, R₁₀S(O)₂—, R₁₀C(O)—,R₁₀C(S)—, R₁₀R₁₁NC(O)—, R₁₀R₁₁NC(S)—R₁₀OC(O)—;

R₄, R₅ and R₆ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;

R₇ and R₈ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynylor haloalkynyl;

R₉ is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each which is unsubstituted or substituted with one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

R₁₀, R₁₁, R₁₂ and R₁₃ are each independently hydrogen, alkyl, haloalkyl,thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,haloalkenyl, alkynyl or haloalkynyl; or

R₁₀ together with R₁₁ form ═O, ═S or ═NR₂; or

R₁₂ together with R₁₃ form ═O, ═S or ═NR₂;

W is O, S or NR₂;

n is 1-4; and

m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formulae III-1.001 to III-1.025 and III-2.001-III-2.018:

Compounds III-1.001 to III-1.025 Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵R¹⁶ 1.001 3,5-Cl₂ C—H C—H C—H C—H N H CH₂C(O)NHCH₂CF₃ 1.002 3,5-Cl₂ C—HC—H C—H C—H N H CH₂CF₃ 1.003 3,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂CO₂CH₃1.004 3,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂CO₂H 1.005 3,5-(CF₃)₂ C—H C—HC—H C—H N CH₃ CH₂C(O)NHCH₂CF₃ 1.006 3,5-(CF₃)₂ C—H C—H C—H C—H N HCH₂C(O)NHCH₂CF₃ 1.007 3,5-(CF₃)₂ C—H C—H C—H C—H N H CH₂CH₂SCH₃ 1.0083,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.009 3,5-(CF₃)₂ C—HC—H C—H C—H C—H H CH₂CH₂SCH₃ 1.010 3,5-(CF₃)₂ C—H C—H C—H C—H C—H HCH₂CF₃ 1.011 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.012 3,5-Cl₂C—H C—H C—H C—H C—H H CH₂CF₃ 1.013 3,5-Cl₂ C—H C—H C—H C—H C—H HCH₂CH₂SCH₃ 1.014 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.0153-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CF₃ 1.016 3-Cl, 5-CF₃ C—H C—H C—HC—H C—H H CH₂CH₂SCH₃ 1.017 3,5-Cl₂ C—H C—H C—Me C—H C—Me HCH₂C(O)NHCH₂CF₃ 1.018 3,5-Cl₂ C—H C—H C—Me C—H C—Me H CH₂CF₃ 1.0193,5-Cl₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃ 1.020 3,5-(CF₃)₂ C—H C—H C—MeC—H C—Me H CH₂C(O)NHCH₂CF₃ 1.021 3,5-(CF₃)₂ C—H C—H C—Me C—H C—Me HCH₂CF₃ 1.022 3,5-(CF₃)₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃ 1.023 3-Cl,5-CF₃ C—H C—H C—Me C—H C—Me H CH₂C(O)NHCH₂CF₃ 1.024 3-Cl, 5-CF₃ C—H C—HC—Me C—H C—Me H CH₂CF₃ 1.025 3-Cl, 5-CF₃ C—H C—H C—Me C—H C—Me HCH₂CH₂SCH₃

Compounds III-2.001 to III-2.018 Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵R¹⁶ 2.001 3,5-Cl₂ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.002 3,5-Cl₂ C—HC—H N C—H C—H H CH₂CF₃ 2.003 3,5-Cl₂ C—H C—H N C—H C—H H CH₂CH₂SCH₃2.004 3,5-(CF₃)₂ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.005 3,5-(CF₃)₂C—H C—H N C—H C—H H CH₂CF₃ 2.006 3,5-(CF₃)₂ C—H C—H N C—H C—H HCH₂CH₂SCH₃ 2.007 3-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.0083-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂CF₃ 2.009 3-Cl, 5-CF₃ C—H C—H N C—HC—H H CH₂CH₂SCH₃ 2.010 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃2.011 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂CF₃ 2.012 3,5-Cl₂ C—H C—H C—H C—HC—H H CH₂CH₂SCH₃ 2.013 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃2.014 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂CF₃ 2.015 3,5-(CF₃)₂ C—H C—HC—H C—H C—H H CH₂CH₂SCH₃ 2.016 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H HCH₂C(O)NHCH₂CF₃ 2.017 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CF₃ 2.0183-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of e isoxazoline compound offormula (IV)

wherein X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of e isoxazoline compound offormula (IVa)

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

iv) an antiparasitic effective amount of an isoxazoline compound offormula (V)

wherein X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

iv) an antiparasitic effective amount of an isoxazoline compound offormula (Va)

or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of at least one isoxazolinecompound of formula (VI):

wherein R¹, R² and R³ are independently H, Cl, F or CF₃;

Y is the diradical group

and

T is a C₁-C₆-alkyl group which is unsubstituted or substituted byhalogen, cyano, nitro, amino, hydroxyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-alkylthio, carboxy, carbamoyl or C₂-C₆-alkanoylgroup which may be unsubstituted or substituted in the alkyl portion byhalogen or a pharmaceutical acceptable salt thereof

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant; and

e) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising

a) an antiparasitic effective amount of an isoxazoline compound offormula (VIa):

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising

a) an antiparasitic effective amount of at least one compound of formula(VII):

wherein

-   -   Y is hydrogen, fluoro, chloro or bromo;    -   R¹ is phenyl substituted with 2-4 substituents selected from        halogen, methyl, difluoromethyl, trifluoromethyl, methoxy,        trifluoromethoxy or trifluoroethoxy;    -   R² is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;

R^(3a) and R^(3b) are independently selected from hydrogen, methyl,ethyl or fluoromethyl; or R^(3a) and R^(3b) together combine with thecarbon to which they are attached to form a cyclopentyl ring or acyclohexyl ring; or a pharmaceutically acceptable salt thereof

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally, a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention(prophylaxis) of parasitic infections and infestations of animalscomprising:

a) an antiparasitic effective amount of an isoxazoline compound offormula (VIIa):

-   -   or a pharmaceutically acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one pharmaceutically acceptable solvent;

d) optionally, an antioxidant;

e) optionally a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the extended release injectable formulations ofpresent invention comprise an antiparasitic effective amount of4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide(Compound of formula IIc).

In another embodiment, the pharmaceutically acceptable polymer in theextended release injectable formulations described above may be acopolymer of polylactides and polyglycolides, and the solvent may be asingle solvent, such as, for example a cyclic carbonate (e.g., ethylenecarbonate or propylene carbonate) or a mixture of solvents comprising,for example, a cyclic carbonate, a glycerol ester (e.g., glyceroltriacetate), and, optionally, a poloxamer (for example, P-124), whichcan function either as a solvent or a surfactant. In yet a furtherembodiment, the extended release formulations described above anantioxidant is present, such as, butylated hydroxytoluene.

The compounds of formula (I) through formula (VIIa) can exist asstereoisomers since there is a chiral center in the molecule. Theindividual stereoisomers are encompassed by the structural formulasdepicted herein. The various stereoisomers include enantiomers,diastereomers and atopisomers. One of skill in the art will understandthat one stereoisomer may be more active and/or may exhibit beneficialproperties relative to the other enantiomer. In addition, the skilledperson in the art knows how to separate, enrich, and/or selectivelyprepare a stereoisomer of the isoxazoline compounds described herein.The isoxazoline compounds described herein contain a chiral quaternarycarbon atom in the five-membered isoxazoline ring (shown by the asterisk(*)); therefore, the compounds will contain at least two possiblestereoisomers. As an example for the compounds of formula (IIc), the twopossible stereoisomers resulting from the quaternary carbon are shown asformula (R)-IIc and (S)-IIc:

The compound of formula (S)-IIc above has the (S) configuration at thechiral carbon atom and the compound of formula (R)-IIc has the (R)configuration.

Molecular depictions drawn herein follow standard conventions fordepicting stereochemistry. To indicate stereo configuration, bondsrising from the plane of the drawing and towards the viewer are denotedby solid wedges wherein the broad end of the wedge is attached to theatom rising from the plane of the drawing towards the viewer. Bondsgoing below the plane of the drawing and away from the viewer aredenoted by dashed wedges wherein the narrow end of the wedge is attachedto the atom further away from the viewer. Constant width lines indicatebonds with a direction opposite or neutral relative to bonds shown withsolid or dashed wedges; constant width lines also depict bonds inmolecules or parts of molecules in which no particular stereoconfiguration is intended to be specified.

Hence, in an another embodiment, the extended release injectableformulations of present invention comprise an antiparasitic effectiveamount of at least one isoxazoline of Formula (I), Formula (II), Formula(IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula (IIe),Formula (IIf), Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa) which is enriched in one enantiomer, ora pharmaceutically acceptable salt thereof.

In one embodiment, the extended release injectable formulations comprisean antiparasitic effective amount of at least one isoxazoline of Formula(I), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula(IId), Formula (IIe), Formula (IIf), Formula (III), Formula (III-1.1001)to Formula (III-1.025), Formula (III-2.001) to Formula (III-2.018),Formula (IV), Formula (IVa), Formula (V), Formula (Va), Formula (VI),Formula (VIa), Formula (VII) or Formula (VIIa), which is enriched anenantiomer that displays significant in vitro and in vivo activity witha favorable toxicity profile (the eutomer) whereas a compound orcomposition enriched in the other enantiomer displays significantly lessin vitro and in vivo activity (the distomer), or a pharmaceuticallyacceptable salt thereof. In one embodiment of the invention, the morebiologically active enantiomer of the compound of Formula IIc isbelieved to be compound of Formula (S)-IIc shown above, which has the(S)-configuration at the chiral carbon atom. Similarly, the morebiologically active enantiomers of isoxazoline compounds of formulaeFormula (I), Formula (II), Formula (IIa), Formula (IIb), Formula (IId),Formula (IIe), Formula (IIf), Formula (III), Formula (III-1.1001) toFormula (III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula(IV), Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula(VIa), Formula (VII) or Formula (VIIa) are believed to have the (S)configuration at the chiral carbon of the isoxazoline ring.

In an embodiment, the compounds of formulae Formula (I), Formula (II),Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula(IIe), Formula (IIf), Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa) present in the compositions of theinvention are enriched in one enantiomer over the other enantiomer in aweight:weight ratio of at least 1.5:1. In another embodiment, thecompounds of Formula (I), Formula (II), Formula (IIa), Formula (IIb),Formula (IIc), Formula (IId), Formula (IIe), Formula (IIf), Formula(III), Formula (III-1.1001) to Formula (III-1.025), Formula (III-2.001)to Formula (III-2.018), Formula (IV), Formula (IVa), Formula (V),Formula (Va), Formula (VI), Formula (VIa), Formula (VII) or Formula(VIIa) present in the compositions of the invention are enriched in oneenantiomer in a weight:weight ratio of at least 2:1, at least 5:1 or atleast 10:1.

In another embodiment, the compounds of Formula (I), Formula (II),Formula (IIa), Formula (IIb), Formula (IIc), Formula (IId), Formula(IIe), Formula (IIf), Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa) present in the compositions of theinvention are essentially pure enantiomers. Thus, in another embodiment,the invention provides extended release injectable compositions thatcomprise the essentially pure enantiomers of the compounds of Formula(I), Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula(IId), Formula (IIe), Formula (IIf), Formula (III), Formula (III-1.1001)to Formula (III-1.025), Formula (III-2.001) to Formula (III-2.018),Formula (IV), Formula (IVa), Formula (V), Formula (Va), Formula (VI),Formula (VIa), Formula (VII) or Formula (VIIa).

In one embodiment, the composition of the invention comprises a compoundof formula (I), that is substantially enriched in an enantiomer. Theterm “substantially enriched” is meant wherein the weight:weight ratiois at least about 1.5:1 or higher in favor of the desired enantiomer. Inanother embodiment, the extended release injectable compositions of theinvention comprise a compound of formula (I), that is substantiallyenriched in the (S)-enantiomer. In another embodiment, the extendedrelease injectable compositions of the invention comprise a compound offormula (I) that is substantially enriched in the (R)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of formula (I), that is enriched in the (S)-enantiomer in aweight:weight ratio of at least about 2:1, (S) to (R), or greater. Inyet another embodiment, the compositions of the invention comprise acompound of formula (I) that is enriched in the (S)-enantiomer in aweight:weight ratio of at least about 5:1, (S) to (R), or greater. Instill another embodiment, the compositions of the invention comprise acompound of formula (I), that is enriched in the (S)-enantiomer in aweight:weight ratio of at least about 10:1, (S) to (R), or greater. Instill another embodiment, the compositions of the invention comprise acompound of formula (I), that is essentially the pure (S)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of formula (I), that is enriched in the (R)-enantiomer in aweight:weight ratio is at least approximately 2:1, (R) to (S), orgreater. In yet another embodiment, the compositions of the inventioncomprise a compound of formula (I), that is enriched in the(R)-enantiomer in a weight:weight ratio of at least about 5:1, (R) to(S), or greater. In still another embodiment, the compositions of theinvention comprise a compound of formula (I), that is enriched in the(R)-enantiomer in a weight:weight ratio of at least about 10:1, (R) to(S), or greater. In still another embodiment, the compositions of theinvention comprise a compound of formula (I) that is essentially thepure R-enantiomer.

In one embodiment, the composition of the invention comprises a compoundof formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) that issubstantially enriched in an enantiomer. In another embodiment, theextended release injectable compositions of the invention comprise acompound of formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf)that is substantially enriched in the (S)-enantiomer. In anotherembodiment, the extended release injectable compositions of theinvention comprise a compound of formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf) that is substantially enriched in the(R)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf)that is enriched in the (S)-enantiomer in a weight:weight ratio of atleast about 2:1, (S) to (R), or greater. In yet another embodiment, thecompositions of the invention comprise a compound of formula (II),(IIa), (IIb), (IIc), (IId), (IIe) or (IIf) that is enriched in the(S)-enantiomer in a weight:weight ratio of at least about 5:1, (S) to(R), or greater. In still another embodiment, the compositions of theinvention comprise a compound of formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf) that is enriched in the (S)-enantiomer in aweight:weight ratio of at least about 10:1, (S) to (R), or greater. Instill another embodiment, the compositions of the invention comprise acompound of formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf)that is essentially the pure (S)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of formula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf)that is enriched in the (R)-enantiomer in a weight:weight ratio is atleast approximately 2:1, (R) to (S), or greater. In yet anotherembodiment, the compositions of the invention comprise a compound offormula (II), (IIa), (IIb), (IIc), (IId), (IIe) or (IIf) that isenriched in the (R)-enantiomer in a weight:weight ratio of at leastabout 5:1, (R) to (S), or greater. In still another embodiment, thecompositions of the invention comprise a compound of formula (II),(IIa), (IIb), (IIc), (IId), (IIe) or (IIf) that is enriched in the(R)-enantiomer in a weight:weight ratio of at least about 10:1, (R) to(S), or greater. In still another embodiment, the compositions of theinvention comprise a compound of formula (II), (IIa), (IIb), (IIc),(IId), (IIe) or (IIf) that is essentially the pure (R)-enantiomer.

In one embodiment, the composition of the invention comprises a compoundof formula (IIc) that is substantially enriched in an enantiomer. Inanother embodiment, the extended release injectable compositions of theinvention comprise a compound of formula (IIc) that is substantiallyenriched in the (S)-enantiomer. In another embodiment, the extendedrelease injectable compositions of the invention comprise a compound offormula (IIc) that is substantially enriched in the (R)-enantiomer.

In another embodiment, this invention comprises racemic mixtures, forexample, approximately equal amounts of the enantiomers of Formulae (I),Formula (II), Formula (IIa), Formula (IIb), Formula (IIc), Formula(IId), Formula (IIe), Formula (IIf), Formula (III), Formula (III-1.1001)to Formula (III-1.025), Formula (III-2.001) to Formula (III-2.018),Formula (IV), Formula (IVa), Formula (V), Formula (Va), Formula (VI),Formula (VIa), Formula (VI) or Formula (VIIa).

When enantiomerically enriched, one enantiomer is present in greateramounts than the other, and the extent of enrichment may be defined byan expression of enantiomeric excess (“ee”), which is defined as(2×-1)-100%, where x is the mole fraction of the dominant enantiomer inthe mixture (e.g., an ee of 20% corresponds to a 60:40 ratio ofenantiomers). In some embodiments, the compositions of the inventioncomprise compounds that have at least a 50% enantiomeric excess. Inother embodiments, the compositions of the invention comprise compoundsthat have at least a 75% enantiomeric excess, at least a 90%enantiomeric excess, or at least a 94% enantiomeric excess of the moreactive isomer. Of particular note are enantiomerically pure embodimentsof the more active isomer (the eutomer).

Compounds of this invention can exist as one or more conformationalisomers due to restricted rotation about the amide bond bonded to thearyl or heteroaryl ring (e.g. the amide bonded to the naphthyl group inFormula (IIc)). This invention comprises mixtures of conformationalisomers. In addition, this invention includes compounds that areenriched in one conformer relative to others.

It will be appreciated that in addition to the chiral carbon atom in theisoxazoline ring of the compounds of formulae (I) to (VIIa), certaincompounds may include other chiral centers in one or more substituents.Thus, these compounds will have a greater number of possiblestereoisomers (e.g. diastereomers). All possible stereoisomers areencompassed in the extended release injectable compositions of theinvention.

Accordingly, in one embodiment of the invention, the compositionscomprise a compound of Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa), that is enriched in the (S)-enantiomerin a weight:weight ratio is at least approximately 2:1, (S) to (R), orgreater. In yet another embodiment, the compositions of the inventioncomprise a compound of Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa), that is enriched in the (S)-enantiomerin a weight:weight ratio of at least about 5:1, (S) to (R), or greater.In still another embodiment, the compositions of the invention comprisea compound of Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa), that is enriched in the (S)-enantiomerin a weight:weight ratio of at least approximately 10:1, (S) to (R), orgreater. In still another embodiment, the compositions of the inventioncomprise a compound of Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa), that is essentially the pure(S)-enantiomer.

In another embodiment of the invention, the compositions comprise acompound of Formula (III), Formula (III-1.1001) to Formula (III-1.025),Formula (III-2.001) to Formula (III-2.018), Formula (IV), Formula (IVa),Formula (V), Formula (Va), Formula (VI), Formula (VIa), Formula (VII) orFormula (VIIa), that is enriched in the (R)-enantiomer in aweight:weight ratio is at least approximately 2:1, (R) to (S), orgreater. In yet another embodiment, the compositions of the inventioncomprise a compound of Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa), that is enriched in the (R)-enantiomerin a weight:weight ratio of at least about 5:1, (R) to (S), or greater.In still another embodiment, the compositions of the invention comprisea compound of Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (Via),Formula (VII) or Formula (VIIa), that is enriched in the (R)-enantiomerin a weight:weight ratio of at least approximately 10:1, (R) to (S), orgreater. In still another embodiment, the compositions of the inventioncomprise a compound of Formula (III), Formula (III-1.1001) to Formula(III-1.025), Formula (III-2.001) to Formula (III-2.018), Formula (IV),Formula (IVa), Formula (V), Formula (Va), Formula (VI), Formula (VIa),Formula (VII) or Formula (VIIa), that is essentially the pure(R)-enantiomer.

In another embodiment, the extended release injectable formulations ofpresent invention comprise an antiparasitic effective amount of at leastone isoxazoline disclosed in WO 2007/079162, WO 2007/075459 and US2009/0133319, WO 2007/070606 and US 2009/0143410, WO 2009/003075, WO2009/002809, WO 2009/024541, WO 2005/085216 and US 2007/0066617 WO2008/122375, WO 2014/439475 A1 and WO2012 120135A1, all of which areincorporated herein by reference in their entirety.

In yet another embodiment, the extended release injectable formulationsof present invention comprise an antiparasitic effective amount of atleast one isoxazoline compound described in WO 2009/02451A2 and WO2011/075591A1, both incorporated herein by reference in their entirety.

In one embodiment, the compositions of the invention may comprise about5 to about 50% (w/w) of an isoxazoline active agent. In anotherembodiment, the compositions may comprise about 5 to about 30% (w/w) ofthe isoxazoline active agent. In yet other embodiments, the compositionsmay include about 5 to about 20% (w/w) or about 5 to about 15% (w/w) ofthe isoxazoline active agent. In another embodiment, the compositions ofthe invention may comprise about 10 to about 40% (w/w) or 10 to about30% (w/w) of an isoxazoline active agent.

In another embodiment, the compositions may comprise about 10 to about20% of an isoxazoline active agent. In yet another embodiment, thecompositions of the invention may comprise about 15% to about 40% (w/w),about 15% to about 35% (w/w) or about 15% to about 30% (w/w) of anisoxazoline compound. In yet another embodiment, the compositions of theinvention will comprise about 20 to about 30% (w/w), about 20 to about25% (w/w) or about 25 to about 30% (w/w) of the isoxazoline activeagent.

In one embodiment, the compositions of the invention comprise about 1 toabout 40% (w/w) of a pharmaceutically acceptable polymer, including abiodegradable polymer. In other embodiments, the compositions compriseabout 1 to about 30% (w/w) or about 1 to about 20% (w/w) of apharmaceutically acceptable polymer. In another embodiment, thecompositions comprise about 1 to about 15% (w/w) or about 1 to about 10%(w/w) of a pharmaceutically acceptable polymer. In another embodiment,the compositions comprise about 5 to about 20% (w/w) or about 5 to about15% (w/w) of a pharmaceutically acceptable polymer. In anotherembodiment, the compositions comprise about 10 to about 20% (w/w) orabout 10 to about 15% (w/w) of a pharmaceutically acceptable polymer. Inanother embodiment, the compositions comprise about 7 to about 13% (w/w)or about 8 to about 15% (w/w) of a pharmaceutically acceptable polymer.In yet another embodiment, the compositions of the invention compriseabout 1 to about 7% (w/w), about 1 to about 5% (w/w) or about 3 to about7% (w/w) of a pharmaceutically acceptable polymer.

In one embodiment, the compositions of the invention may comprise about30% to about 90% (w/w) of a solvent or mixture of solvents. In anotherembodiment, the compositions of the invention may comprise about 40% toabout 90% (w/w) of a solvent or mixture of solvents. In yet anotherembodiment, the compositions comprise about 40% to about 80% (w/w),about 50% to about 80% (w/w) or about 45% to about 80% (w/w) of asolvent or a mixture of solvents. In yet another embodiment, thecompositions of the invention comprise about 60% to about 80% (w/w) orabout 65% to about 80% (w/w) of a solvent or a mixture of solvents. Instill another embodiment, the compositions may comprise about 65% toabout 75% (w/w) or about 70% to about 80% (w/w) of a solvent or amixture of solvents.

In another embodiment, the compositions of the invention may compriseabout 0.01% to about 10% (w/w) of a pharmaceutically acceptableadditive, excipient or mixtures thereof. In other embodiments, thecompositions may comprise about 0.01% to about 5% (w/w), about 0.1% toabout 10% (w/w) or about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the compositions of the invention may compriseabout 0.01% to about 5% (w/w) of an antioxidant. In other embodiments,the compositions may comprise about 0.01% to about 3% (w/w) or about0.01 to about 2% (w/w) of an antioxidant.

The pharmaceutically acceptable polymers in the extended releaseinjectable formulations, include, but are not limited to, polylactides,polyglycolides, polycaprolactones, polyanhydrides, polyamides,polyurethanes, polyesteramides, polyorthoesters, polydioxanones,polyacetals, polyketals, polycarbonates, polyorthocarbonates,polyphosphazenes, pseudo poly(amides), polyhydroxyalcanoates,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), poly(amino acids),poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan, andcopolymers, terpolymers, or combinations or mixtures therein includingcopolymers of polylactides, polycaprolactones, polyglycolides (e.g.,poly(lactide-co-glycolide) and copolymers of polyethylene glycol orrnethoxy polyethylene glycol with one or more of polycaprolactone,polylactide or any of the other polymers/polymer groups mentioned above.Also included are derivatives of pharmaceutically acceptable polymerssuch as hydroxylated derivatives including polycaprolactone diols andthe like.

In one embodiment, the pharmaceutically acceptable polymer is abiodegradable polymer. In another embodiment, the pharmaceuticallyacceptable biodegradable polymer can have one or more or all of thefollowing characteristics: be bioerodible by cellular action,biodegradable by action of non-living body fluid components, soften whenexposed to heat but return to the original state when cooled and arecapable of substantially dissolving or dispersing in a water-misciblecarrier or solvent to form a solution or dispersion. Upon contact withan aqueous fluid the polymer is capable of assisting in the formation ofthe film coated or encapsulated liquid or solid (which will contain theactive agent in the present invention). The kinds of polymers suitablefor the present composition generally include any having the foregoingcharacteristics. Examples of biodegradable polymers include, but are notlimited to, polylactides, polycaprolactones, polyglycolides,polyorthoesters, polyurethanes, polyphasphazenes, pseudo poly(amides),and copolymers thereof.

It will be apparent to the skilled person that the molecular weight of apolymer is not a discreet number but can be presented in a molecularweight range. The average molecular weight of a polymer may be found bytechniques familiar to persons of skill in the art, for example, sizeexclusion chromatography with molecular weight standards, or the like.The molecular weight range of a polymer can impact the physicalcharacteristics of the material and the way that it interacts with theactive agent. Accordingly the molecular weight range of the polymer mayimpact the characteristics of the extended release compositions of theinvention. For example, in some embodiments depending on the activeagent and solvents included, one may see an earlier release of theisoxazoline active agent when the weight average molecular weight rangeis from about 5 to about 20 kDa (kilo daltons) or from about 7 to about15 kDa. A later release of the isoxazoline active agent may be observedwhen the weight average molecular weight is between about 30 to about 70kDa (e.g., about 40 to about 70 kDa or about 45 to about 60 kDa) or fromabout 90 to about 200 kDa (e.g., about 100 to about 150 or about 105 toabout 130 kDa). In some embodiments, a combination of polymers havingdifferent average molecular weights may provide a release rate thatcombines the effect of the different polymers used.

Inherent viscosity (IV) in polymer chemistry is a viscometric method formeasuring molecular weight. It is defined as the ratio of the naturallogarithm of the relative viscosity to the mass concentration of thepolymer and is based on the flow time of a polymer solution through anarrow capillary. As used herein with respect to the molecular weightrange of a pharmaceutically acceptable polymer, the term “low molecularweight” (LMW) refers to polymer with an inherent viscosity in the rangeof 0.05-0.29 dL/g; the term “medium molecular weight” refers to apolymer with an inherent viscosity in the range of 0.3-0.55 dL/g; andhigh molecular weight refers to a polymer with an inherent viscosity inthe range of 0.55-1.0 dL/g. In another embodiment, the pharmaceuticallyacceptable polymer in the extended release formulations of the inventionwill have an inherent viscosity of about 0.10-0.20 dL/g. In anotherembodiment, the pharmaceutically acceptable polymer in the extendedrelease formulations will have an inherent viscosity of about 0.35-0.50.

In some embodiments, the extended release injectable formulations of theinvention comprise polylactides, polycaprolactones, polyglycolides andcopolymers thereof. In another embodiment, the compositions include apoly(lactide-co-glycolide) copolymer (“PLGA”). PLGA copolymers may havedifferent molecular weight ranges and may also have differentweight:weight ratios of lactide to glycolide. This ratio, may affect theproperties of the copolymer and the way that it interacts with theactive agent. Since a lactide group contains an additional methyl groupin the sidechain compared with a glycolide, this change may affect theconformation of the polymer and change the way in which the polymerinteracts with the isoxazoline active agent (and/or other active agentcombined with the isoxazoline). Although not bound by theory, in oneembodiment, the compositions of the invention having a higher lactide toglycolide ratio (e.g. 75:25 compared with 50:50) result in an increasein hydrogen bonding between the active agent and the polymer, leading tobetter solubility of the active agent in vivo. This effect improves theinjection site reaction and allows for the extendable release injectablecompositions to include a higher amount of the active agent, which willtranslate to a longer duration of efficacy.

In one embodiment of the invention, when the pharmaceutically acceptablepolymer is PLGA, the ratio of lactide to glycolide is about 30:70 toabout 99:1. In another embodiment of the invention where thepharmaceutically acceptable polymer is PLGA, the ratio of lactide toglycolide is about 40:60 to about 80:15. In another embodiment of theinvention where the pharmaceutically acceptable polymer is PLGA, theratio of lactide to glycolide is about 40:60 to about 60:40. In anotherembodiment of the invention where the pharmaceutically acceptablepolymer is PLGA, the ratio of lactide to glycolide is about 70:30 toabout 80:20. In another embodiment of the invention, where thepharmaceutically acceptable polymer is PLGA, the ratio of lactide toglycolide is about 50:50. In another embodiment of the invention, wherethe pharmaceutically acceptable polymer is PLGA, the ratio of lactide toglycolide is about 75:25.

In some embodiments, the amount of PLGA contained in the extendedrelease injectable formulation of the invention is about 1% to about 30%(w/w), In another embodiment, the compositions comprise about 1 to about20% (w/w) of PLGA. In another embodiment, the compositions compriseabout 5 to about 20%, about 8% to about 20% (w/w) or about 10 to about20% (w/w). In another embodiment, the compositions comprise about 5 toabout 15% (w/w) of PLGA. In other embodiments, the amount of PLGAcontained in the extended release injectable formulation of theinvention is from about 3% to about 15% (w/w) or is from about 10% toabout 15% (w/w). In yet another embodiment, the compositions compriseabout 7 to about 13% or about 8 to about 15% (w/w) of PLGA.

In some embodiments, the weight:weight ratio of—PLGA to the isoxazolineactive agent is greater than or equal to about 1:1, for example, fromabout 1.1:1 to about 20:1; e.g., about 1:1 to about 10:1, about 1.1:1 toabout 10:1 or about 2:1 to about 5:1. In other embodiments, theweight:weight ratio of PLGA to the isoxazoline active agent is about1.2:1 to about 5:1. In another embodiment, the weight:weight ratio ofPLGA to the isoxazoline active agent is about 1.2:1 to about 2:1. In yetanother embodiment, the weight:weight ratio of PLGA to the isoxazolineactive agent is about 1.2:1 to about 1.3:1.

In other embodiments the weight:weight ratio of PLGA to the isoxazolineactive agent is about 1.5:1 to about 1:1.5. In other embodiments, theratio of the isoxazoline active agent to PLGA is from about 1.25:1 toabout 1:1:25.

The solvents used in the extended release injectable formulations of theinvention may be a single or a blend of solvents. Non-limiting examplesof these solvents include alcohols such as ethanol, 1-propanol,isopropanol, glycol ethers (e.g., including, but limited to,diethyleneglycol monoethyl ether (DGME, Transcutol®), butyl diglycol,dipropylene glycol n-butyl ether, ethyleneglycol monoethyl ether,ethyleneglycol monomethyl ether, dipropylene glycol monomethyl ether,propylene glycol monomethyl ether, propylene glycol monoethyl ether, andthe like), liquid polyethylene glycols (PEGs) including, but not limitedto, PEG 200, PEG 300 and PEG 400; propylene glycol, glycerol, glycerolesters including glycerol triacetate (triacetin), cyclic carbonates(e.g., ethylene carbonate and propylene carbonate), 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide (DMI), dimethylacetamide (DMA),dimethyl formamide (DMF), caprolactam, glycerol formal, acetone,dimethylsulfoxide (DMSO), ethyl acetate, ethyl lactate, benzyl benzoate,or a mixture of at least two of these solvents.

In one embodiment, the compositions of the invention may include one ormore poloxamers as a solvent or surfactant. Poloxamers are a family ofsynthetic block copolymers of ethylene oxide and propylene oxide.Poloxamers may be liquid, a milky white paste or a powder and arerepresented by the following structure:

where a is an integer between 2 and 130 and b is an integer between 15and 67 (see, U.S. Pat. No. 3,740,421). Poloxamer are available fromcommercial sources such as BASF and Croda. An example of a poloxamer isP-124 which is a solid at room temperature. In one embodiment, poloxamerP-124 has the values a=12 and b=20. Other poloxamers include P-128 (a=38and b=29), P-181 (a=3 and b=30) P-188 (a=80 and b=27), P-237 (a=64 andb=37), P338 (a=141 and b=44) and P407 (a=101 and b=56,). In someembodiments, the amount of poloxamer, when present, is from about 0.5%to about 20 (w/w). In other embodiments, the compositions may have, whenpresent, about 1% to about 20% (w/w), about 1% to about 10% (w/w) orfrom about 1 to about 5% (w/w). In other embodiments, the amount ofpoloxamer, when present, is from about 1% to about 3% (w/w).

In one embodiment, the compositions of the invention comprise a solventor mixture of solvents that is miscible with water. Solvents that aremiscible with water are well known and include certain alcohols, liquidpolyethylene glycols (PEGs), certain poloxamers, glycols and glycolethers and polar aprotic solvents. Alcohols that are miscible with waterinclude, but are not limited to ethanol, isopropanol, n-propanol,Solketal (isopropylidene glycerol) or glycerol formal. Polar aproticsolvents include, but are not limited to, amides such asdimethylacetamide, dimethylformamide, 2-pyrrolidone, N-alkylpyrrolidonessuch as N-methylpyrrolidone and N-octylpyrrolidone, dimethylisosorbide,dimethylsulfoxide, cyclic carbonates including propylene carbonate andethylene carbonate, and certain ketones such as acetone and the like.Glycol ethers include, but are not limited to, diethyleneglycolmonoethyl ether (DGME, Transcutol®), butyl diglycol, dipropylene glycoln-butyl ether, ethyleneglycol monoethyl ether, ethyleneglycol monomethylether, dipropylene glycol monomethyl ether, propylene glycol monomethylether, propylene glycol monoethyl ether, and the like.

In one embodiment, the extended release formulations of the inventioncomprise a polar protic solvent including, but not limited to, analcohol such as ethanol, isopropanol or a glycol or glycol ether.

In another embodiment, the extended release injectable formulations ofthe invention comprise a polar aprotic solvent such asN-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide or propylenecarbonate.

In yet another embodiment of the invention, the compositions of theinvention include non-water miscible solvents (e.g. not completelymiscible with water, although they may have some solubility in water).Non-limiting examples of these solvents include 1-butanol, 2-butanol,1-pentanol, 3-pentanol, benzyl alcohol, methylethylketone (MEK),triacetin, lipids, triglycerides including medium chain triglyceridessuch C₈-C₁₀ triglycerides such as capric/caprilic triglycerides,propylene glycol derivatives (e.g. propylene glycol monolaurate),caprylocaproyl polyoxyl-8 glycerides (Labrasol) (non-ionic waterdispersible surfactant, isopropyl myristate, oils such as castor oil,soybean oil or other vegetable oils or derivatives thereof such asepoxidized or hydrogenated vegetable oils such as epoxidized soybean oilor hydrogenated castor oil, or a mixture of at least two of thesesolvents.

In another embodiment, the composition of the invention may includeneutral oils as a solvent. Neutral oils are triglycerides offractionated plant fatty acids with chain lengths of C₈ to C₁₀. Twocommercially available products are known as MIGLYOL® 810 andMIGLYOL®812. In another embodiment, the neutral oil is a triglyceride offractionated plant fatty acids with chain lengths of C₈ and C₁₀ combinedwith linoleic acid (about 4-5%). A commercially available product isknown as MIGLYOL® 818. In yet another embodiment, the neutral oil is aglycerin ester of fractionated plant fatty acids with chain lengths ofC₈ and C₁₀ combined with succinic acid. A commercially available productis known as MIGLYOL® 829. In yet another embodiment, the neutral oil isa propylene glycol fatty acid ester. In one embodiment, the neutral oilmay be a propylene glycol diester of saturated plant fatty acids withchain lengths of C₈ and C₁₀. A commercially available product is knownas MIGLYOL® 840 (propylene glycol dicaprylate/dicaprate). In yet anotherembodiment, the solvent may be a mixture of two or more neutral oils.

It will be appreciated that blends of solvents may be used as thesolvent of the extended release injectable formulations. In oneembodiment, the compositions of the invention may contain a blend of awater-miscible solvent with a solvent that is not water miscible. Forexample, in one embodiment, the solvent may be a mixture of a cycliccarbonate such as propylene carbonate with triacetin. Of course, otherblends of a water-miscible solvent and a non-water miscible solvent arepossible. In one embodiment, the water-miscible solvent in the solventblend may be a water-miscible alcohol such as ethanol or isopropanol,glycerol formal or Solketal, an amide such as 2-pyrrolidone,N-methylpyrrolidone, dimethylisosorbide or dimethylacetamide, a glycolsuch as propylene glycol, glycerol or a glycol ether.

In another embodiment, the non-water miscible solvent in the solventblend may be triacetin, benzyl alcohol, a triglyceride including C₈-C₁₀triglycerides such as capric/caprilic triglycerides, propylene glycolderivatives (e.g. propylene glycol monolaurate), caprylocaproylpolyoxyl-8 glycerides (Labrasol); a propylene glycol fatty acid diester,and the like.

In one embodiment, the solvent may be a blend of a water-misciblesolvent and a non-water miscible solvent in a weight:weight ratio ofbetween about 10 to 1 to about 1 to 10, water-miscible solvent tonon-water miscible solvent. In another embodiment, the weight:weightratio of the water-miscible solvent to non-water miscible solvent may befrom about 5 to 1 to about 1 to 1. In another embodiment, theweight:weight ratio of the water-miscible solvent to non-water misciblesolvent may be from about 3 to 1 to about 1 to 1. In another embodiment,the weight:weight ratio of the water-miscible solvent to non-watermiscible solvent may be from about 3 to 1 to about 2 to 1 or about 2 to1 to about 1 to 1.

In yet another embodiment, the solvent may be a blend of awater-miscible solvent and a non-water miscible solvent in aweight:weight ratio of about 1 to 2 or about 1 to 3, water-misciblesolvent to non-water miscible solvent. In another embodiment, theweight:weight ratio of the water-miscible solvent to non-water misciblesolvent may be from about 1 to about 5, 1 to about 7.

In one embodiment, the solvent may be a blend of cyclic carbonate (e.g.,propylene carbonate) and glycerol ester (e.g., triacetin) in aweight:weight ratio of between about 10 to 1 to about 1 to 1, cycliccarbonate (e.g., propylene carbonate) to glycerol ester (e.g.,triacetin). In one embodiment, the solvent may be a blend of cycliccarbonate (e.g., propylene carbonate) and glycerol ester (e.g.,triacetin) in a weight:weight ratio of between about 5 to 1 to about 1to 1, cyclic carbonate (e.g. propylene carbonate) to glycerol ester(e.g., triacetin). In another embodiment, the solvent may be a blend ofcyclic carbonate (e.g., propylene carbonate) and glycerol ester (e.g.,triacetin) in a weight:weight ratio of between about 3 to 1 to about 1to 1, cyclic carbonate (e.g. propylene carbonate) to glycerol ester(e.g., triacetin). In yet another embodiment, the solvent may be a blendof cyclic carbonate (e.g., propylene carbonate) and glycerol ester(e.g., triacetin) in a weight:weight ratio of between about 2 to 1 toabout 1 to 1 or about 3:1 to about 2:1, cyclic carbonate (e.g. propylenecarbonate) to glycerol ester (e.g., triacetin). In other embodiments,the range for the weight:weight ratio of cyclic carbonate (e.g.propylene carbonate) to glycerol ester (e.g., triacetin) is 1.5:1 toabout 15:1 or from about 2:1 to about 6:1.

Surfactants may be present in the inventive formulations atconcentrations of about 0.1% to about 10% (w/w), about 1% to about 10%(w/w) or about 5% to about 10% (w/w). More typically, surfactants may bepresent at concentrations of about 0.1% to about 5% (w/w) or about 1 toabout 5% (w/w). Examples of surfactants that may be used in thecompositions include, but are not limited to, glyceryl monooleate,polyoxyethylene sorbitan fatty acid esters, sorbitan esters 30 includingsorbitan monooleate (Span® 20), polyvinyl alcohol, polysorbatesincluding polysorbate 20 and polysorbate 80, d-α-tocopheryl polyethyleneglycol 1000 succinate (TPGS), sodium lauryl sulfate, co-polymers ofethylene oxide and propylene oxide (e.g. poloxamers such as LUTROL® F87and the like), polyethylene glycol castor oil derivatives includingpolyoxyl 35 castor oil (Cremophor® EL), polyoxyl 40 hydrogenated castoroil (Cremophor® RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor®RH60); propylene glycol monolaurate (LAUROGLYCOL®); glyceride estersincluding glycerol caprylate/caprate (CAPMUL® MCM), polyglycolizedglycerides (GELUCIRE®), PEG 300 caprylic/capric glycerides (Softigen®767), PEG 400 caprylic/capric glycerides (Labrasol®), PEG 300 oleicglycerides (Labrafil® M-1944CS), PEG 300 linoleic glycerides (Labrafil®M-2125CS); polyethylene glycol stearates and polyethylene glycol hydroxystearates including polyoxyl 8 stearate (PEG 400 monostearate), polyoxyl40 stearate (PEG 1750 monostearate, and the like). Polyethylene glycolstearates (synonyms include macrogol stearates, polyoxylstearates,polyoxyethylene stearates, ethoxylated stearates; CAS No. 9004-99-3,9005-08-7) are mixtures of mono- and distearate esters of mixedpolyoxyethylene polymers. Polyethylene glycol hydroxystearate is amixture of mono- and diesters of hydroxystearic acid with polyethyleneglycols. One polyethylene glycol hydroxystearate that may be used in thecompositions is polyethylene glycol 12-hydroxystearate. In anotherembodiment, the inventive formulations may include the surfactantpolyethylene glycol 15 12-hydroxystearate (Kolliphor® HS 15 from BASF),a mixture of mono- and diesters of 12-hydroxystearic acid with 15 molesof ethylene oxide. Again, these compounds, as well as their amounts arewell known in the art. In another embodiment of the invention, theinventive formulations may include polyoxyl 35 castor oil (Kolliphor®EL) as a surfactant. In other embodiments, the inventive formulationsmay include polyoxyl 40 hydrogenated castor oil (Kolliphor® RH 40) orpolyoxyl 60 hydrogenated castor oil as surfactants. The formulations ofthe invention may also include a combination of surfactants.

The inventive formulations may contain other inert ingredients such asantioxidants, preservatives, or pH stabilizers. These compounds are wellknown in the formulation art. Antioxidants such as vitamin E, alphatocopherol, ascorbic acid, ascorbyl palmitate, citric acid, fumaricacid, malic acid, sodium ascorbate, sodium metabisulfate, sodiummetabisulfite, n-propyl gallate, BHA (butylated hydroxy anisole), BHT(butylated hydroxy toluene), BHA and citric acid, monothioglycerol,tert-butyl hydroquinone (TBHQ), and the like, may be added to thepresent formulation. The antioxidants are generally added to theformulation in amounts of from about 0.01 to about 5.0%, based upontotal weight of the formulation, with about 0.05 to about 2.0% beingespecially preferred. In another embodiment, the formulation preferablycontains about 0.05 to about 1.0% (w/w) of an antioxidant.

Preservatives, such as the parabens (methylparaben, ethylparaben,butylparaben and/or propylparaben), are suitably used in the formulationin amounts ranging from about 0.01 to about 2.0%, with about 0.05 toabout 1.0% being especially preferred. Other preservatives includebenzalkonium chloride, benzethonium chloride, benzoic acid, benzylalcohol, bronopol, cetrimide, chlorhexidine, chlorobutanol,chlorocresol, cresol, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuricnitrate, potassium sorbate, sodium benzoate, sodium propionate, sorbicacid, thimerosal, and the like. Preferred ranges for these compoundsinclude from about 0.01 to about 5%.

Compounds which stabilize the pH of the formulation are alsocontemplated. Again, such compounds are well known to a practitioner inthe art as well as how to use these compounds. Buffering systemsinclude, for example, systems selected from the group consisting ofacetic acid/acetate, malic acid/malate, citric acid/citrate, tartaricacid/tartrate, lactic acid/lactate, phosphoric acid/phosphate,glycine/glycimate, tris, glutamic acid/glutamates and sodium carbonate.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 5 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 1% to about 40 (w/w) pharmaceutically acceptable polymer;

c) about 40% to 95% (w/w) of a pharmaceutically acceptable solvent ormixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 5 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 1% to about 30 (w/w) pharmaceutically acceptable polymer;

c) about 40% to 95% (w/w) of a pharmaceutically acceptable solvent ormixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 10% to about 40 (w/w) pharmaceutically acceptable polymer;

c) about 30% to 85% (w/w) of a pharmaceutically acceptable solvent ormixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 1% to about 30 (w/w) pharmaceutically acceptable polymer;

c) about 30% to 85% (w/w) of a pharmaceutically acceptable solvent ormixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain other embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 12% to about 38% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 40% to about 85% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain other embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 1% to about 20% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 40% to about 85% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 20 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 15% to about 40% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 50% to about 80% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 20 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 1% to about 10% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 50% to about 80% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 20 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 15% to about 38% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 60% to about 80% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prevention ofparasitic infections and infestations of animals comprising:

a) about 20 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa);

b) about 3% to about 7% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 60% to about 80% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In other embodiments where the compositions comprise an isoxazolineactive agent which is enriched in the more active enantiomer (theeutomer) the present invention provides for extended release injectableformulations for the treatment and/or prevention of parasitic infectionsand infestations of animals comprising:

a) about 5 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 1% to about 30% (w/w) pharmaceutically acceptable polymer;

c) about 40% to 95% (w/w) of a pharmaceutically acceptable solvent ormixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In other embodiments where the compositions comprise an isoxazolineactive agent which is enriched in the more active enantiomer (theeutomer) the present invention provides for extended release injectableformulations for the treatment and/or prevention of parasitic infectionsand infestations of animals comprising:

a) about 5 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 1% to about 28% (w/w) pharmaceutically acceptable polymer;

c) about 40% to 95% (w/w) of a pharmaceutically acceptable solvent ormixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain other embodiments where the compositions comprise anisoxazoline active agent which is enriched in the more active enantiomer(the eutomer), the present invention provides for extended releaseinjectable formulations for the treatment and/or prevention of parasiticinfections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 1% to about 20% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 50% to about 95% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain other embodiments where the compositions comprise anisoxazoline active agent which is enriched in the more active enantiomer(the eutomer), the present invention provides for extended releaseinjectable formulations for the treatment and/or prevention of parasiticinfections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 5% to about 20% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 60% to about 95% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain other embodiments where the compositions comprise anisoxazoline active agent which is enriched in the more active enantiomer(the eutomer), the present invention provides for extended releaseinjectable formulations for the treatment and/or prevention of parasiticinfections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 1% to about 10% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 60% to about 95% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain other embodiments where the compositions comprise anisoxazoline active agent which is enriched in the more active enantiomer(the eutomer), the present invention provides for extended releaseinjectable formulations for the treatment and/or prevention of parasiticinfections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 3% to about 20% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 70% to about 95% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain other embodiments where the compositions comprise anisoxazoline active agent which is enriched in the more active enantiomer(the eutomer), the present invention provides for extended releaseinjectable formulations for the treatment and/or prevention of parasiticinfections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 1% to about 5% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 70% to about 95% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention where the compositionscomprise an isoxazoline active agent enriched in the more activeenantiomer (the eutomer), the invention provides for extended releaseinjectable formulations for the treatment and/or prevention of parasiticinfections and infestations of animals comprising:

a) about 10 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 8% to about 30% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 60% to about 90% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention where the compositionscomprise an isoxazoline active agent enriched in the more activeenantiomer (the eutomer), the invention provides for extended releaseinjectable formulations for the treatment and/or prevention of parasiticinfections and infestations of animals comprising:

a) about 10 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa) enrichedin the (S)-enantiomer;

b) about 3% to about 7% (w/w) of a pharmaceutically acceptablebiodegradable polymer;

c) about 60% to about 90% (w/w) of a pharmaceutically acceptable solventor mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa), such as,a compound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 40% (w/w) of a pharmaceutically acceptable polymer;

c) about 40% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of any of Formulae I-VIIa), such as,a compound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) about 40% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 10% to about 40% (w/w) of a pharmaceutically acceptablepolymer;

c) about 30% to about 85% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) about 30% to about 85% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 20 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 15% to about 40% (w/w) of a pharmaceutically acceptablepolymer;

c) about 50% to about 80% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 20 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about % to about 10% (w/w) of a pharmaceutically acceptable polymer;

c) about 50% to about 80% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 10% to about 40% (w/w) of a pharmaceutically acceptablepolymer;

c) about 60% to about 85% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 3% to about 7% (w/w) of a pharmaceutically acceptable polymer;

c) about 60% to about 85% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In yet another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 12% to about 38% (w/w) of a PLGA polymer;

c) about 55% to about 85% (w/w) of a mixture of a water miscible solventand a water immiscible solvent;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In yet another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 5% (w/w) of a PLGA polymer;

c) about 55% to about 85% (w/w) of a mixture of a water miscible solventand a water immiscible solvent;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 10% to about 35% (w/w) of a PLGA polymer;

c) about 60% to about 85% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol including ethanol, isopropanol, glycerol formaland Solketal; and an amide and the water immiscible solvent is selectedfrom the group consisting of benzyl alcohol, a glycerol ester, atriglyceride and a propylene glycol ester;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 15 to 30% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 7% (w/w) of a PLGA polymer;

c) about 60% to about 85% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol including ethanol, isopropanol, glycerol formaland Solketal; and an amide and the water immiscible solvent is selectedfrom the group consisting of benzyl alcohol, a glycerol ester, atriglyceride and a propylene glycol ester;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 28% (w/w) of a pharmaceutically acceptable polymer;

c) about 40% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VIIa), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 30% (w/w) of a pharmaceutically acceptable polymer;

c) about 40% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In certain embodiments the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VI), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 20% (w/w) of a pharmaceutically acceptable polymer;

c) about 50% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VI), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 5% to about 20% (w/w) of a pharmaceutically acceptable polymer;

c) about 60% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VI), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 10% (w/w) of a pharmaceutically acceptable polymer;

c) about 60% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VI), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 3% to about 20% (w/w) of a pharmaceutically acceptable polymer;

c) about 70% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 5 to 15% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VI), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 1% to about 5% (w/w) of a pharmaceutically acceptable polymer;

c) about 70% to about 95% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 10 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VI), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 8% to about 28% (w/w) of a pharmaceutically acceptable polymer;

c) about 60% to about 90% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment the present invention provides for extendedrelease injectable formulations for the treatment and/or prophylaxis ofparasitic infections and infestations of animals comprising:

a) about 10 to 20% (w/w) of an isoxazoline active agent, such as, forexample, any of the isoxazoline compounds provided for in theembodiments above (e.g., a compound of Formulae I-VI), such as, acompound of the formula:

or a pharmaceutically acceptable salt thereof,

b) about 3% to about 7% (w/w) of a pharmaceutically acceptable polymer;

c) about 60% to about 90% (w/w) of solvent or mixture of solvents;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

Another embodiment of the present invention is an extended releaseinjectable formulation for the treatment and/or prevention of parasiticinfections and infestations of animals consisting essentially of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) a pharmaceutically acceptable polymer;

c) at least one solvent or a mixture of solvents;

d) optionally, an antioxidant;

e) optionally, a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting essentiallyof:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 1% to about 30% (w/w) of a PLGA polymer;

c) about 40% to about 98% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal; d) optionally, about 0.01% to about 2% (w/w)of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting essentiallyof:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 1% to about 20% (w/w) of a PLGA polymer;

c) about 40% to about 98% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal;

d) optionally, about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting essentiallyof:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 5% to about 20% (w/w) of a PLGA polymer;

c) about 40% to about 90% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal;

d) optionally, about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting essentiallyof:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 5% to about 15% (w/w) of a PLGA polymer;

c) about 50% to about 95% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal; d) optionally, about 0.01% to about 2% (w/w)of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting essentiallyof:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 1% to about 10% (w/w) of a PLGA polymer;

c) about 50% to about 95% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal;

d) optionally, about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof

Another embodiment of the present invention is an extended releaseinjectable formulation for the treatment and/or prevention of parasiticinfections and infestations of animals consisting of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) a pharmaceutically acceptable biodegradable polymer;

c) at least one solvent wherein said solvent is a polar solvent misciblein water;

d) optionally, an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 1% to about 30% (w/w) of a PLGA polymer;

c) about 40% to about 98% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal;

d) optionally, about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) 0.1% to about 10% (w/w) ofa surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 1% to about 20% (w/w) of a PLGA polymer;

c) about 40% to about 98% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal;

d) optionally, about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 5% to about 20% (w/w) of a PLGA polymer;

c) about 40% to about 90% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal; d) optionally, about 0.01% to about 2% (w/w)of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 1% to about 10% (w/w) of a PLGA polymer;

c) about 50% to about 98% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal;

d) optionally, about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the present invention provides an extendedrelease injectable formulation for the treatment and/or prevention ofparasitic infections and infestations of animals consisting of:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, such as, for example, any of the isoxazoline compounds providedfor in the embodiments above (e.g., a compound of any of FormulaeI-VIIa), and optionally at least one additional active agent asidentified in this application;

b) about 5% to about 15% (w/w) of a PLGA polymer;

c) about 50% to about 95% (w/w) of a mixture of a water miscible solventand a water immiscible solvent, wherein the water miscible solvent isselected from the group consisting of a cyclic carbonate,dimethylisosorbide, dimethylsulfoxide, 2-pyrrolidone,N-methylpyrrolidone, N-octylpyrrolidone, a liquid polyethylene glycol, apoloxamer, an alcohol, Solketal and an amide and the water immisciblesolvent is selected from the group consisting of benzyl alcohol, aglycerol ester, glycerol formal, a triglyceride, a propylene glycolester and glycerol formal;

d) optionally, about 0.01% to about 2% (w/w) of an antioxidant;

e) optionally, about 0.1% to about 10% (w/w) of a surfactant; and

f) optionally, about 0.1% to about 5% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

In another embodiment, the pharmaceutically acceptable polymer in theextended release injectable formulations described above may be acopolymer of a polylactides and polyglycolides and the solvent may be asingle solvent, such as, for example a cyclic carbonate (e.g., ethylenecarbonate or propylene carbonate) or a mixture of solvents comprising,for example, a cyclic carbonate, a glycerol ester (e.g., glyceroltriacetate), and, optionally, a poloxamer (for example, P-124), whichcan function either as a solvent or a surfactant. In yet a furtherembodiment, the extended release injectable formulations, describedabove, may further include an antioxidant, such as, butylatedhydroxytoluene (BHT).

Further embodiments of the invention are any of the extended releaseinjectable formulations provided for above wherein: the ratio of PLGA tothe isoxazoline active agent to the copolymer of polylactides andpolyglycolides is about 1.5:1 to about 1:1.5 (weight:weight); the weightaverage molecular weight of the copolymer of polylactides andpolyglycolides is about 5 kDa to about 20 kDa; and the concentration ofthe copolymer of polylactides and polyglycolides is about 8% (w/w) toabout 20% (w/w) (e.g., 12.5% (w/w) or 13% (w/w)). In a furtherembodiment, any of the extended release injectable formulations providedfor above may further comprise 0.5% (w/w) to about 20% (w/w) ofpoloxamer (e.g., about 1% (w/w) to about 3% (w/w)). In yet a furtherembodiment, the copolymer of polylactides and polyglycolides may have alactide to glycolide ratio of about 75:25 (weight:weight).

The extended release formulations of the invention are prepared byadding to the solvent or solvent mixture, any non-polymer excipients(e.g. if present antioxidants, surfactants, etc.), followed by additionof the active ingredient(s) with mixing. When the active ingredient andnon-active excipients are fully solubilized, the pharmaceuticallyacceptable polymer(s) are added with mixing until completely dissolved.Of course, the composotions may be prepared by other appropriateprocesses known in the art as long as the resulting formulation is ahomogeneous liquid formulation suitable for use.

In this disclosure and in the claims, terms such as “comprises,”“comprising,” “containing” and “having” and the like can have themeaning ascribed to them in U.S. Patent law and can mean “includes,”“including,” and the like; “consisting essentially of” or “consistsessentially” likewise has the meaning ascribed in U.S. Patent law andthe term is open-ended, allowing for the presence of more than thatwhich is recited so long as basic or novel characteristics of that whichis recited is not changed by the presence of more than that which isrecited, but excludes prior art embodiments. The term “consisting of”excludes any element, step or ingredient not specified in the claims.

DEFINITIONS

Terms used herein will have their customary meaning in the art unlessspecified otherwise. The organic moieties mentioned in the definitionsof the variables of formula (I) are—like the term halogen—collectiveterms for individual listings of the individual group members. Theprefix C_(n)-C_(m) indicates in each case the possible number of carbonatoms in the group.

The term “extended release” or “extended release formulation” or“extended release composition” as used herein means a dosage form thatis formulated in such a manner to make the active agent(s) containedtherein to be available over an extended period of time due to theinteraction of the formulation components in combination with thenatural pharmacokinetic or pharmacodynamic characteristics of the activeagent(s). This definition is consistent with the use of the term knownand accepted in the veterinary field as described in the article“Terminology Challenges: Defining Modified Release Dosage Forms inVeterinary Medicine” by Marilyn N. Martinez, Danielle Lindquist andSanja Modric (Journal of Pharmaceutical Sciences, vol. 99, no. 8, August2010).

For example, the extended release formulations according to the presentinvention would be understood to provide an efficacy of at least 90%against fleas and/or ticks for at least 3 months as described herein.

The term “animal” is used herein to include all mammals, birds and fishand also include all vertebrate animals. Animals include, but are notlimited to, cats, dogs, cattle, chickens, cows, deer, goats, horses,llamas, pigs, sheep and yaks. It also includes an individual animal inall stages of development, including embryonic and fetal stages. In someembodiments, the animal will be a non-human animal.

The term “essentially pure” is used herein to indicate that a compoundor an enantiomer is at least about 90% (w/w) pure, at least about 95%(w/w), or at least about 98% (w/w) pure, or higher.

The term “alkyl” refers to saturated straight, branched, cyclic,primary, secondary or tertiary hydrocarbons, including those having 1 to20 atoms. In some embodiments, alkyl groups will include C₁-C₁₂, C₁-C₁₀,C₁-C₈, C₁-C₆ or C₁-C₄ alkyl groups. Examples of C₁-C₁₀ alkyl include,but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,2-ethylhexyl, nonyl and decyl and their isomers. C₁-C₄-alkyl means forexample methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl.

Cyclic alkyl groups or “cycloalkyl”, which are encompassed by alkylinclude those with 3 to 10 carbon atoms having single or multiplecondensed rings. In some embodiments, cycloalkyl groups include C₄-C₇ orC₃-C₄ cyclic alkyl groups. Non-limiting examples of cycloalkyl groupsinclude adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like.

The alkyl groups described herein can be unsubstituted or substitutedwith one or more moieties selected from the group consisting of alkyl,halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, alkyl- ordialkylamino, amido, arylamino, alkoxy, aryloxy, nitro, cyano, azido,thiol, imino, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl,sulfamoyl, ester, phosphonyl, phosphinyl, phosphoryl, phosphine,thioester, thioether, acid halide, anhydride, oxime, hydrazine,carbamate, phosphoric acid, phosphate, phosphonate, or any other viablefunctional group that does not inhibit the biological activity of thecompounds of the invention, either unprotected, or protected asnecessary, as known to those skilled in the art, for example, as taughtin Greene, et al., Protective Groups in Organic Synthesis, John Wileyand Sons, Third Edition, 1999, hereby incorporated by reference.

Terms including the term “alkyl” such as “alkylcycloalkyl,”“cycloalkylalkyl,” “alkylamino,” or “dialkylamino” will be understood tocomprise an alkyl group as defined above linked to the other functionalgroup, where the group is linked to the compound through the last grouplisted, as understood by those of skill in the art.

The term “alkenyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon double bond. In some embodiments,alkenyl groups may include C₂-C₂₀ alkenyl groups. In other embodiments,alkenyl includes C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkenyl groups.In one embodiment of alkenyl, the number of double bonds is 1-3, inanother embodiment of alkenyl, the number of double bonds is one or two.Other ranges of carbon-carbon double bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. “C₂-C₁₀-alkenyl” groups may include more than one double bondin the chain. Examples include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

“Alkynyl” refers to both straight and branched carbon chains which haveat least one carbon-carbon triple bond. In one embodiment of alkynyl,the number of triple bonds is 1-3; in another embodiment of alkynyl, thenumber of triple bonds is one or two. In some embodiments, alkynylgroups include from C₂-C₂₀ alkynyl groups. In other embodiments, alkynylgroups may include C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkynyl groups.Other ranges of carbon-carbon triple bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. For example, the term “C₂-C₁₀-alkynyl” as used herein refersto a straight-chain or branched unsaturated hydrocarbon group having 2to 10 carbon atoms and containing at least one triple bond, such asethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl,n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl,n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl,n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl,3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl,n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl,n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl,n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl,3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl,4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term “haloalkyl” refers to an alkyl group, as defined herein, whichis substituted by one or more halogen atoms. For example C₁-C₄-haloalkylincludes, but is not limited to, chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl andthe like.

The term “haloalkenyl” refers to an alkenyl group, as defined herein,which is substituted by one or more halogen atoms.

The term “haloalkynyl” refers to an alkynyl group, as defined herein,which is substituted by one or more halogen atoms.

“Alkoxy” refers to alkyl-O—, wherein alkyl is as defined above.Similarly, the terms “alkenyloxy,” “alkynyloxy,” “haloalkoxy,”“haloalkenyloxy,” “haloalkynyloxy,” “cycloalkoxy,” “cycloalkenyloxy,”“halocycloalkoxy,” and “halocycloalkenyloxy” refer to the groupsalkenyl-O—, alkynyl-O—, haloalkyl-O—, haloalkenyl-O—, haloalkynyl-O—,cycloalkyl-O—, cycloalkenyl-O—, halocycloalkyl-O—, andhalocycloalkenyl-O—, respectively, wherein alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, andhalocycloalkenyl are as defined above. Examples of C₁-C₆-alkoxy include,but are not limited to, methoxy, ethoxy, C₂H₅—CH₂O—, (CH₃)₂CHO—,n-butoxy, C₂H₅—CH(CH₃)O—, (CH₃)₂CH—CH₂O—, (CH₃)₃CO—, n-pentoxy,1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy,1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxyand the like.

The term “alkylthio” refers to alkyl-S—, wherein alkyl is as definedabove. Similarly, the terms “haloalkylthio,” “cycloalkylthio,” and thelike, refer to haloalkyl-S— and cycloalkyl-S— where haloalkyl andcycloalkyl are as defined above.

The term “alkylsulfinyl” refers to alkyl-S(O)—, wherein alkyl is asdefined above.

Similarly, the term “haloalkylsulfinyl” refers to haloalkyl-S(O)— wherehaloalkyl is as defined above.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—, wherein alkyl is asdefined above. Similarly, the term “haloalkylsulfonyl” refers tohaloalkyl-S(O)₂— where haloalkyl is as defined above.

The term alkylamino and dialkylamino refer to alkyl-NH— and (alkyl)₂N—where alkyl is as defined above. Similarly, the terms “haloalkylamino”refers to haloalkyl-NH— where haloalkyl is as defined above.

The terms “alkylcarbonyl,” “alkoxycarbonyl,” “alkylaminocarbonyl,” and“dialkylaminocarbonyl” refer to alkyl-C(O)—, alkoxy-C(O)—,alkylamino-C(O)— and dialkylamino-C(O)— where alkyl, alkoxy, alkylaminoand dialkylamino are as defined above.

Similarly, the terms “haloalkylcarbonyl,” “haloalkoxycarbonyl,”“haloalkylaminocarbonyl,” and “dihaloalkylaminocarbonyl” refer to thegroups haloalkyl-C(O)—, haloalkoxy-C(O)—, haloalkylamino-C(O)— anddihaloalkylamino-C(O)— where haloalkyl, haloalkoxy, haloalkylamino anddihaloalkylamino are as defined above.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring or multiple condensed rings. In someembodiments, aryl groups include C₆-C₁₀ aryl groups. Aryl groupsinclude, but are not limited to, phenyl, biphenyl, naphthyl,tetrahydronaphthyl, phenylcyclopropyl and indanyl. Aryl groups may beunsubstituted or substituted by one or more moieties selected fromhalogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl,halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy,haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy,cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio,haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl,alkenylsulfinyl, alkynyl-sulfinyl, haloalkylsulfinyl,haloalkenylsulfinyl, haloalkynylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, haloalkyl-sulfonyl,haloalkenylsulfonyl, haloalkynylsulfonyl, alkylamino, alkenylamino,alkynylamino, di(alkyl)amino, di(alkenyl)-amino, di(alkynyl)amino, ortrialkylsilyl.

The terms “aralkyl” or “arylalkyl” refers to an aryl group that isbonded to the parent compound through a diradical alkylene bridge,(—CH₂—)_(n), where n is 1-12 and where “aryl” is as defined above.

“Heteroaryl” refers to a monovalent aromatic group of from 1 to 15carbon atoms, preferably from 1 to 10 carbon atoms, having one or moreoxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfurheteroatoms may optionally be oxidized. Such heteroaryl groups can havea single ring (e.g., pyridyl or furyl) or multiple condensed ringsprovided that the point of attachment is through a heteroaryl ring atom.Preferred heteroaryls include pyridyl, piridazinyl, pyrimidinyl,pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinnyl, furanyl, thienyl, furyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl benzofuranyl,and benzothienyl. Heteroaryl rings may be unsubstituted or substitutedby one or more moieties as described for aryl above. The term“heteroarylene” (where the heteroaryl group is a bridging group) shouldbe construed accordingly.

“Heterocyclyl,” “heterocyclic” or “heterocyclo” refer to fully saturatedor unsaturated, cyclic groups, for example, 3 to 7 membered monocyclicor 4 to 7 membered monocyclic; 7 to 11 membered bicyclic, or 10 to 15membered tricyclic ring systems, which have one or more oxygen, sulfuror nitrogen heteroatoms in ring, preferably 1 to 4 or 1 to 3heteroatoms. The nitrogen and sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom ofthe ring or ring system and may be unsubstituted or substituted by oneor more moieties as described for aryl groups above.

Exemplary monocyclic heterocyclic groups include, but are not limitedto, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl,4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfonyl, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include, but are not limited to,indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl,quinuclidinyl, quinolinyl, tetra-hydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),tetrahydroquinolinyl and the like. The term “heterobicyclylene” (wherethe bicyclic heterocyclic group is a bridging group) should be construedaccordingly.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

Halogen means the atoms fluorine, chlorine, bromine and iodine. Thedesignation of “halo” (e.g. as illustrated in the term haloalkyl) refersto all degrees of substitutions from a single substitution to a perhalosubstitution (e.g. as illustrated with methyl as chloromethyl (—CH₂Cl),dichloromethyl (—CHCl₂), trichloromethyl (—CCl₃)).

By the term “enriched” is meant when the weight:weight ratio is at leastapproximately 1.05 or higher in favor of one enantiomer over the other.Preferably, the weight:weight ratio is at least approximately 1.05 orhigher in favor of the enantiomer that displays significant in vitro andin vivo activity (the eutomer).

Stereoisomers and Polymorphic Forms

As noted above, it will be appreciated by those of skill in the art thatcertain compounds within the compositions of the invention may exist andbe isolated as optically active and racemic forms. Compounds having oneor more chiral centers, including at a sulfur atom, may be present assingle enantiomers or diastereomers or as mixtures of enantiomers and/ordiastereomers. For example, it is well known in the art that sulfoxidecompounds may be optically active and may exist as single enantiomers orracemic mixtures. In addition, compounds within the compositions of theinvention may include one or more chiral centers, which results in atheoretical number of optically active isomers. Where compounds withinthe compositions of the invention include n chiral centers, thecompounds may comprise up to 2^(n) optical isomers. The presentinvention encompasses compositions comprising the specific enantiomersor diastereomers of each compound as well as mixtures of differentenantiomers and/or diastereomers of the compounds of the invention thatpossess the useful properties described herein. In addition, theinvention encompasses compositions comprising one or more conformationalisomers (e.g. rotamers) as well as mixtures of conformational isomers.Conformational isomers of the isoxazoline compounds may be produced by arestriction of rotation about the amide bond bonded to the aryl orheteroaryl ring (e.g. the amide bonded to the naphthyl group in Formula(IIc)). The optically active forms can be prepared by, for example,resolution of the racemic forms by selective crystallization techniques,by synthesis from optically active precursors, by chiral synthesis, bychromatographic separation using a chiral stationary phase or byenzymatic resolution.

In addition, the compounds within the compositions of the invention mayexist as hydrates or solvates, in which a certain stoichiometric amountof water or a solvent is associated with the molecule in the crystallineform. The compositions of the invention may include hydrates andsolvates of the active agents. In some embodiments, the compositions ofthe invention may include up to 15% (w/w), up to 20% (w/w), or up to 30%(w/w) of a particular solid form.

Salts

Also contemplated within the scope of the invention are acid or basesalts, where applicable, of the compounds of the invention provided forherein.

The term “acid salt” contemplates salts of the compounds with allpharmaceutically acceptable inorganic or organic acids. Inorganic acidsinclude mineral acids such as hydrohalic acids such as hydrobromic acidand hydrochloric acid, sulfuric acid, phosphoric acids and nitric acid.Organic acids include all pharmaceutically acceptable aliphatic,alicyclic and aromatic carboxylic acids, dicarboxylic acids,tricarboxylic acids and fatty acids. In one embodiment of the acids, theacids are straight chain or branched, saturated or unsaturated C₁-C₂₀aliphatic carboxylic acids, which are optionally substituted by halogenor by hydroxyl groups, or C₆-C₁₂ aromatic carboxylic acids. Examples ofsuch acids are carbonic acid, formic acid, acetic acid, propionic acid,isopropionic acid, valeric acid, ca-hydroxy acids such as glycolic acidand lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid,and salicylic acid. Examples of dicarboxylic acids include oxalic acid,malic acid, succinic acid, tartaric acid, fumaric acid, and maleic acid.An example of a tricarboxylic acid is citric acid. Fatty acids includeall pharmaceutically acceptable saturated or unsaturated aliphatic oraromatic carboxylic acids having 4 to 24 carbon atoms. Examples includebutyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmiticacid, stearic acid, oleic acid, linoleic acid, linolenic acid, andphenylsteric acid. Other acids include gluconic acid, glycoheptonic acidand lactobionic acid.

The term “base salt” contemplates salts of the compounds with allpharmaceutically acceptable inorganic or organic bases, includinghydroxides, carbonates or bicarbonates of alkali metal or alkaline earthmetals. Salts formed with such bases include, for example, the alkalimetal and alkaline earth metal salts, including, but not limited to, asthe lithium, sodium, potassium, magnesium or calcium salts. Salts formedwith organic bases include the common hydrocarbon and heterocyclic aminesalts, which include, for example, ammonium salts (NH4⁺), alkyl- anddialkylammonium salts, and salts of cyclic amines such as the morpholineand piperidine salts.

In another embodiment, the extended release injectable formulations ofpresent invention comprise an effective amount of at least oneisoxazoline or a pharmaceutically acceptable salt thereof in combinationat least one other active agent. In one embodiment, the extended releaseinjectable compositions comprise an effective amount of at least oneisoxazoline compound of formula (I) to (VIIa), or a pharmaceuticallyacceptable salt thereof, in combination with at least one other activeagent that is systemically-active.

Additional veterinary/pharmaceutical active ingredients may be used withthe compositions of the invention. In some embodiments, the additionalactive agents may include, but are not limited to, acaricides,anthelmintics, anti-parasitics and insecticides. Anti-parasitic agentscan include both ectoparasiticidal and/or endoparasiticidal agents.

Veterinary pharmaceutical agents that may be included in thecompositions of the invention are well-known in the art (see e.g. Plumb'Veterinary Drug Handbook, 5^(th) Edition, ed. Donald C. Plumb, BlackwellPublishing, (2005) or The Merck Veterinary Manual, 9^(th) Edition,(January 2005)) and include but are not limited to acarbose,acepromazine maleate, acetaminophen, acetazolamide, acetazolamidesodium, acetic acid, acetohydroxamic acid, acetylcysteine, acitretin,acyclovir, albendazole, albuterol sulfate, alfentanil, allopurinol,alprazolam, altrenogest, amantadine, amikacin sulfate, aminocaproicacid, aminopentamide hydrogen sulfate, aminophylline/theophylline,amiodarone, amitriptyline, amlodipine besylate, ammonium chloride,ammonium molybdenate, amoxicillin, clavulanate potassium, amphotericin Bdesoxycholate, amphotericin B lipid-based, ampicillin, amprolium,antacids (oral), antivenin, apomorphione, apramycin sulfate, ascorbicacid, asparaginase, aspiring, atenolol, atipamezole, atracuriumbesylate, atropine sulfate, aurnofin, aurothioglucose, azaperone,azathioprine, azithromycin, baclofen, barbituates, benazepril,betamethasone, bethanechol chloride, bisacodyl, bismuth subsalicylate,bleomycin sulfate, boldenone undecylenate, bromides, bromocriptinemesylate, budenoside, buprenorphine, buspirone, busulfan, butorphanoltartrate, cabergoline, calcitonin salmon, calcitrol, calcium salts,captopril, carbenicillin indanyl sodium, carbimazole, carboplatin,carnitine, carprofen, carvedilol, cefadroxil, cefazolin sodium,cefixime, clorsulon, cefoperazone sodium, cefotaxime sodium, cefotetandisodium, cefoxitin sodium, cefpodoxime proxetil, ceftazidime, ceftiofursodium, ceftiofur, ceftiaxone sodium, cephalexin, cephalosporins,cephapirin, charcoal (activated), chlorambucil, chloramphenicol,chlordiazepoxide, chlordiazepoxide+/−clidinium bromide, chlorothiazide,chlorpheniramine maleate, chlorpromazine, chlorpropamide,chlortetracycline, chorionic gonadotropin (HCG), chromium, cimetidine,ciprofloxacin, cisapride, cisplatin, citrate salts, clarithromycin,clemastine fumarate, clenbuterol, clindamycin, clofazimine,clomipramine, claonazepam, clonidine, cloprostenol sodium, clorazepatedipotassium, clorsulon, cloxacillin, codeine phosphate, colchicine,corticotropin (ACTH), cosyntropin, cyclophosphamide, cyclosporine,cyproheptadine, cytarabine, dacarbazine, dactinomycin/actinomycin D,dalteparin sodium, danazol, dantrolene sodium, dapsone, decoquinate,deferoxamine mesylate, deracoxib, deslorelin acetate, desmopressinacetate, desoxycorticosterone pivalate, detomidine, dexamethasone,dexpanthenol, dexraazoxane, dextran, diazepam, diazoxide (oral),dichlorphenamide, diclofenac sodium, dicloxacillin, diethylcarbamazinecitrate, diethylstilbestrol (DES), difloxacin, digoxin,dihydrotachysterol (DHT), diltiazem, dimenhydrinate, dimercaprol/BAL,dimethyl sulfoxide, dinoprost tromethamine, diphenylhydramine,disopyramide phosphate, dobutamine, docusate/DSS, dolasetron mesylate,domperidone, dopamine, doramectin, doxapram, doxepin, doxorubicin,doxycycline, edetate calcium disodium.calcium EDTA, edrophoniumchloride, enalapril/enalaprilat, enoxaparin sodium, enrofloxacin,ephedrine sulfate, epinephrine, epoetin/erythropoietin, eprinomectin,epsiprantel, erythromycin, esmolol, estradiol cypionate, ethacrynicacid/ethacrynate sodium, ethanol (alcohol), etidronate sodium, etodolac,etomidate, euthanasia agents w/pentobarbital, famotidine, fatty acids(essential/omega), felbamate, fentanyl, ferrous sulfate, filgrastim,finasteride, fipronil, florfenicol, fluconazole, flucytosine,fludrocortisone acetate, flumazenil, flumethasone, flunixin meglumine,fluorouracil (5-FU), fluoxetine, fluticasone propionate, fluvoxaminemaleate, fomepizole (4-MP), furazolidone, furosemide, gabapentin,gemcitabine, gentamicin sulfate, glimepiride, glipizide, glucagon,glucocorticoid agents, glucosamine/chondroitin sulfate, glutamine,glyburide, glycerine (oral), glycopyrrolate, gonadorelin, grisseofulvin,guaifenesin, halothane, hemoglobin glutamer-200 (OXYGLOBIN®), heparin,hetastarch, hyaluronate sodium, hydrazaline, hydrochlorothiazide,hydrocodone bitartrate, hydrocortisone, hydromorphone, hydroxyurea,hydroxyzine, ifosfamide, imidacloprid, imidocarb dipropinate,impenem-cilastatin sodium, imipramine, inamrinone lactate, insulin,interferon alfa-2a (human recombinant), iodide (sodium/potassium),ipecac (syrup), ipodate sodium, iron dextran, isoflurane, isoproterenol,isotretinoin, isoxsuprine, itraconazole, ivermectin, kaolin/pectin,ketamine, ketoconazole, ketoprofen, ketorolac tromethamine, lactulose,leuprolide, levamisole, levetiracetam, levothyroxine sodium, lidocaine,lincomycin, liothyronine sodium, lisinopril, lomustine (CCNU),lufenuron, lysine, magnesium, mannitol, marbofloxacin, mechlorethamine,meclizine, meclofenamic acid, medetomidine, medium chain triglycerides,medroxyprogesterone acetate, megestrol acetate, melarsomine, melatonin,meloxican, melphalan, meperidine, mercaptopurine, meropenem, metformin,methadone, methazolamide, methenamine mandelate/hippurate, methimazole,methionine, methocarbamol, methohexital sodium, methotrexate,methoxyflurane, methylene blue, methylphenidate, methylprednisolone,metoclopramide, metoprolol, metronidaxole, mexiletine, mibolerlone,midazolam milbemycin oxime, mineral oil, minocycline, misoprostol,mitotane, mitoxantrone, morphine sulfate, moxidectin, naloxone,mandrolone decanoate, naproxen, narcotic (opiate) agonist analgesics,neomycin sulfate, neostigmine, niacinamide, nitazoxanide, nitenpyram,nitrofurantoin, nitroglycerin, nitroprusside sodium, nizatidine,novobiocin sodium, nystatin, octreotide acetate, olsalazine sodium,omeprozole, ondansetron, opiate antidiarrheals, orbifloxacin, oxacillinsodium, oxazepam, oxibutynin chloride, oxymorphone, oxytretracycline,oxytocin, pamidronate disodium, pancreplipase, pancuronium bromide,paromomycin sulfate, parozetine, pencillamine, general informationpenicillins, penicillin G, penicillin V potassium, pentazocine,pentobarbital sodium, pentosan polysulfate sodium, pentoxifylline,pergolide mesylate, phenobarbital, phenoxybenzamine, pheylbutazone,phenylephrine, phenypropanolamine, phenytoin sodium, pheromones,parenteral phosphate, phytonadione/vitamin K-1, pimobendan, piperazine,pirlimycin, piroxicam, polysulfated glycosaminoglycan, ponazuril,potassium chloride, pralidoxime chloride, prazosin,prednisolone/prednisone, primidone, procainamide, procarbazine,prochlorperazine, propantheline bromide, propionibacterium acnesinjection, propofol, propranolol, protamine sulfate, pseudoephedrine,psyllium hydrophilic mucilloid, pyridostigmine bromide, pyrilaminemaleate, pyrimethamine, quinacrine, quinidine, ranitidine, rifampin,s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative, selamectin,selegiline/l-deprenyl, sertraline, sevelamer, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, sodum thiosulfate,somatotropin, sotalol, spectinomycin, spironolactone, stanozolol,streptokinase, streptozocin, succimer, succinylcholine chloride,sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline, terbutaline sulfate, testosterone,tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopentalsodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium,tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate,tocainide, tolazoline, telfenamic acid, topiramate, tramadol,trimcinolone acetonide, trientine, trilostane, trimepraxine tartratew/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid,vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil,vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarinsodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zincacetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the invention, arylpyrazole compounds such asphenylpyrazoles, known in the art may be combined with the isoxazolinecompounds in the extended release injectable compositions of theinvention. Examples of such arylpyrazole compounds include but are notlimited to fipronil, pyriprole, ethiprole and those described in U.S.Pat. Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540;6,685,954 and 6,998,131 (all of which are incorporated herein byreference, each assigned to Merial, Ltd., Duluth, Ga.).

In another embodiment of the invention, one or more macrocyclic lactonesor lactams, which act as an acaricide, anthelmintic agent and/orinsecticide, can be added to the compositions of the invention.

The macrocyclic lactones include, but are not limited to, avermectinssuch as abamectin, dimadectin, doramectin, emamectin, eprinomectin,ivermectin, latidectin, lepimectin, selamectin and ML-1,694,554, andmilbemycins such as milbemectin, milbemycin D, milbemycin oxime,moxidectin and nemadectin. Also included are the 5-oxo and 5-oximederivatives of said avermectins and milbemycins.

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., or Albers-Schonberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alia, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054.

Macrocyclic lactones are either natural products or are semi-syntheticderivatives thereof. The structure of the avermectins and milbemycinsare closely related, e.g., by sharing a complex 16-membered macrocycliclactone ring. The natural product avermectins are disclosed in U.S. Pat.No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosedin U.S. Pat. No. 4,199,569. Mention is also made of U.S. Pat. Nos.4,468,390, 5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390336, EP 0 002 916, and New Zealand Patent No. 237 086, inter alia.Naturally occurring milbemycins are described in U.S. Pat. No. 3,950,360as well as in the various references cited in “The Merck Index” 12^(th)ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey(1996). Latidectin is described in the “International NonproprietaryNames for Pharmaceutical Substances (INN)”, WHO Drug Information, vol.17, no. 4, pp. 263-286, (2003). Semisynthetic derivatives of theseclasses of compounds are well known in the art and are described, forexample, in U.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317,4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596,4,973,711, 4,978,677, 4,920,148 and EP 0 667 054.

In yet another embodiment, the invention provides the extended releaseformulations of the present invention comprising4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide(Compound of formula IIc) in combination with a macrocyclic lactoneactive agent.

In yet another embodiment, the invention provides the extended releaseformulations of the present invention comprising4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamide(Compound of formula IIc) in combination with ivermectin, eprinomectin,selamectin, milbemycin oxime or moxidectin.

In another embodiment, the invention provides the extended releaseformulations of the present invention comprising4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamideenriched in the (S)-enantiomer or as the substantially pure(S)-enantiomer (Compound of formula (S)-IIc) in combination with amacrocyclic lactone active agent.

In yet another embodiment, the invention provides the extended releaseformulations of the present invention comprising4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthalanecarboxamideenriched in the (S)-enantiomer or as the substantially pure(S)-enantiomer (Compound of formula (S)-IIc) in combination withivermectin, eprinomectin, selamectin, milbemycin oxime or moxidectin.

In another embodiment of the invention, the invention comprises anextended release injectable formulation comprising an isoxazolinecompound in combination with systemically-acting compounds from a classof acaricides or insecticides known as insect growth regulators (IGRs).Compounds belonging to this group are well known to the practitioner andrepresent a wide range of different chemical classes. These compoundsall act by interfering with the development or growth of the insectpests. Insect growth regulators are described, for example, in U.S. Pat.Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0 179 022or U.K. 2 140 010 as well as U.S. Pat. Nos. 6,096,329 and 6,685,954 (allincorporated herein by reference).

In one embodiment the IGR is a compound that mimics juvenile hormone.Examples of juvenile hormone mimics include azadirachtin, diofenolan,fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen,tetrahydroazadirachtin and4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one.

In an embodiment, the extended release injectable formulations ofpresent invention comprise an effective amount of at least oneisoxazoline of Formula (I) to (VI), or a pharmaceutically acceptablesalt thereof, in combination with methoprene or pyriproxyfen.

In another embodiment, the IGR compound is a chitin synthesis inhibitor.Chitin synthesis inhibitors include chlorofluazuron, cyromazine,diflubenzuron, fluazuron, flucycloxuron, flufenoxuron, hexaflumoron,lufenuron, tebufenozide, teflubenzuron, triflumoron, novaluron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylureaand 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

In yet another embodiment of the invention, adulticide insecticides andacaricides can also be added to the extended release formulations of thepresent invention. These include pyrethrins (which include cinerin I,cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II andmixtures thereof) and pyrethroids, and carbamates including, but are notlimited to, benomyl, carbanolate, carbaryl, carbofuran, meththiocarb,metolcarb, promacyl, propoxur, aldicarb, butocarboxim, oxamyl,thiocarboxime and thiofanox. In one embodiment, the compositions caninclude permethrin in combination with an isoxazoline active agent.

In some embodiments, the extended release injectable formulations of thepresent invention may include one or more antinematodal agentsincluding, but not limited to, active agents in the benzimidazoles,imidazothiazoles, tetrahydropyrimidines, and organophosphate class ofcompounds. In some embodiments, benzimidazoles including, but notlimited to, thiabendazole, cambendazole, parbendazole, oxibendazole,mebendazole, flubendazole, fenbendazole, oxfendazole, albendazole,cyclobendazole, febantel, thiophanate and its o,o-dimethyl analogue maybe included in the compositions.

In other embodiments, the extended release injectable formulations ofthe present invention may include an imidazothiazole compoundsincluding, but not limited to, tetramisole, levamisole and butamisole.In still other embodiments, the extended release formulations of thepresent invention may include tetrahydropyrimidine active agentsincluding, but not limited to, pyrantel, oxantel, and morantel.

Suitable organophosphate active agents include, but are not limited to,coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos,mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

In other embodiments, the extended release injectable formulations ofthe present invention may include the antinematodal compoundsphenothiazine and piperazine as the neutral compound or in various saltforms, diethylcarbamazine, phenols such as disophenol, arsenicals suchas arsenamide, ethanolamines such as bephenium, thenium closylate, andmethyridine; cyanine dyes including pyrvinium chloride, pyrviniumpamoate and dithiazanine iodide; isothiocyanates including bitoscanate,suramin sodium, phthalofyne, and various natural products including, butnot limited to, hygromycin B, ca-santonin and kainic acid.

In other embodiments, the extended release injectable formulations ofthe present invention of the invention may include antitrematodalagents. Suitable antitrematodal agents include, but are not limited to,the miracils such as miracil D and mirasan; praziquantel, epsiprantel,clonazepam and its 3-methyl derivative, oltipraz, lucanthone,hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil, variousbisphenol compounds known in the art including hexachlorophene,bithionol, bithionol sulfoxide and menichlopholan; varioussalicylanilide compounds including tribromsalan, oxyclozanide,clioxanide, rafoxanide, brotianide, bromoxanide and closantel;triclabendazole, diamfenetide, clorsulon, hetolin and emetine.

Anticestodal compounds may also be advantageously used in the extendedrelease formulations of the present invention of the inventionincluding, but not limited to, praziquantel, epsiprantel, and arecolinein various salt forms, bunamidine, niclosamide, nitroscanate,paromomycin and paromomycin II.

In yet other embodiments, the extended release injectable formulationsof the present invention may include other active agents that areeffective against arthropod parasites. Suitable active agents include,but are not limited to, bromocyclen, chlordane, DDT, endosulfan,lindane, methoxychlor, toxaphene, bromophos, bromophos-ethyl,carbophenothion, chlorfenvinphos, chlorpyrifos, crotoxyphos, cythioate,diazinon, dichlorenthion, diemthoate, dioxathion, ethion, famphur,fenitrothion, fenthion, fospirate, iodofenphos, malathion, naled,phosalone, phosmet, phoxim, propetamphos, ronnel, stirofos, allethrin,cyhalothrin, cypermethrin, deltamethrin, fenvalerate, flucythrinate,permethrin, phenothrin, pyrethrins, resmethrin, benzyl benzoate, carbondisulfide, crotamiton, diflubenzuron, diphenylamine, disulfiram,isobornyl thiocyanato acetate, methoprene, monosulfiram,piperonylbutoxide, rotenone, triphenyltin acetate, triphenyltinhydroxide, deet, dimethyl phthalate, and the compounds1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde (MGK-11),2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione(MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and2-(octylthio)ethanol (MGK-874).

An antiparasitic agent that can be combined with an isoxazolinecompounds in the extended release formulations of the present inventioncan be a biologically active peptide or protein including, but notlimited to, depsipeptides, which act at the neuromuscular junction bystimulating presynaptic receptors belonging to the secretin receptorfamily resulting in the paralysis and death of parasites. In oneembodiment of the depsipeptide, the depsipeptide is emodepside (seeWillson et al., Parasitology, Jan. 2003, 126 (Pt 1):79-86). In anotherembodiment, the depsipeptide is PF1022A or a derivative thereof.

In another embodiment, the extended release injectable formulations ofthe present invention may comprise an active agent from theneonicotinoid class of pesticides. The neonicotinoids bind and inhibitinsect specific nicotinic acetylcholine receptors. In one embodiment,the neonicotinoid insecticidal agent that can be combined with anisoxazoline compound to form an extended release injectable formulationof the invention is imidacloprid. Imidacloprid is a well-knownneonicotinoid active agent and is the key active ingredient in thetopical parasiticide products Advantage®, Advantage® II, K9 Advantix®,and K9 Advantix® II sold by Bayer Animal Health and the oralsoft-chewable formulation Advantus™ from Piedmont Animal Health. Agentsof this class are described, for example, in U.S. Pat. No. 4,742,060 orin EP 0 892 060.

In another embodiment, the extended release injectable formulations ofthe present invention may comprise nitenpyram, another active agent ofthe neonicotinoid class of pesticides. Nitenpyram has the followingchemical structure and is the active ingredient in the oral productCAPSTAR™ Tablets sold by Novartis Animal Health.

Nitenpyram is active against adult fleas when given daily as an oraltablet. Nitenpyram works by interfering with normal nerve transmissionand leads to the death of the insect. Nitenpyram has a very fast onsetof action against fleas. For example, CAPSTAR™ Tablets begin to actagainst fleas in as early as 30 minutes after administration and isindicated for use as often as once a day. However, nitenpyram is onlyknown to be effective when administered orally as a systemicparasiticide, as with CAPSTAR™ Tablets.

In certain embodiments, an insecticidal agent that can be combined withthe extended release formulations of the present invention is asemicarbazone, such as metaflumizone.

In another embodiment, the extended release injectable formulations ofthe present invention may advantageously include a combination ofisoxazoline compounds known in the art. These active agents aredescribed in WO 2007/079162, WO 2007/075459 and US 2009/0133319, WO2007/070606 and US 2009/0143410, WO 2009/003075, WO 2009/002809, WO2009/024541, WO 2005/085216 and US 2007/0066617 and WO 2008/122375, allof which are incorporated herein by reference in their entirety.

In another embodiment of the invention, nodulisporic acid and itsderivatives (a class of known acaricidal, anthelmintic, anti-parasiticand insecticidal agents) may be added to the extended releaseformulations of the present invention. These compounds are used to treator prevent infections in humans and animals and are described, forexample, in U.S. Pat. Nos. 5,399,582, 5,962,499, 6,221,894 and6,399,786, all of which are hereby incorporated by reference in theirentirety. The formulations may include one or more of the knownnodulisporic acid derivatives in the art, including all stereoisomers,such as those described in the patents cited above.

In another embodiment, anthelmintic compounds of the amino acetonitrileclass (AAD) of compounds such as monepantel (ZOLVIX), and the like, maybe added to the extended release formulations of the present inventionThese compounds are described, for example, in WO 2004/024704 and U.S.Pat. No. 7,084,280 (incorporated by reference); Sager et al., VeterinaryParasitology, 2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13Mar. 2008, 176-181.

The compositions of the invention may also include aryloazol-2-ylcyanoethylamino compounds such as those described in U.S. Pat. No.8,088,801 to Soll et al., which is incorporated herein in its entirety,and thioamide derivatives of these compounds, as described in U.S. Pat.No. 7,964,621, which is incorporated herein by reference.

The extended release injectable formulations of the present inventionmay also be combined with paraherquamide compounds and derivatives ofthese compounds, including derquantel (see Ostlind et al., Research inVeterinary Science, 1990, 48, 260-61; and Ostlind et al., Medical andVeterinary Entomology, 1997, 11, 407-408). The paraherquamide family ofcompounds is a known class of compounds that include a spirodioxepinoindole core with activity against certain parasites (see Tet. Lett.1981, 22, 135; J. Antibiotics 1990, 43, 1380, and J. Antibiotics 1991,44, 492). In addition, the structurally related marcfortine family ofcompounds, such as marcfortines A-C, are also known and may be combinedwith the formulations of the invention (see J. Chem. Soc.—Chem. Comm.1980, 601 and Tet. Lett. 1981, 22, 1977). Further references to theparaherquamide derivatives can be found, for example, in WO 91/09961, WO92/22555, WO 97/03988, WO 01/076370, WO 09/004432, U.S. Pat. No.5,703,078 and U.S. Pat. No. 5,750,695, all of which are herebyincorporated by reference in their entirety.

In another embodiment of the invention, the compositions may include aspinosyn active agent produced by the soil actinomyceteSaccharopolyspora spinosa (see, for example Salgado V. L. and Sparks T.C., “The Spinosyns: Chemistry, Biochemistry, Mode of Action, andResistance,” in Comprehensive Molecular Insect Science, vol. 6, pp.137-173, 2005) or a semi-synthetic spinosoid active agent. The spinosynsare typically referred to as factors or components A, B, C, D, E, F, G,H, J, K, L, M, N, O, P, Q, R, S, T, U, V, W, or Y, and any of thesecomponents, or a combination thereof, may be used in the compositions ofthe invention. The spinosyn compound may be a 5,6,5-tricylic ringsystem, fused to a 12-membered macro cyclic lactone, a neutral sugar(rhamnose), and an amino sugar (forosamine). These and other naturalspinosyn compounds, including 21-butenyl spinosyn produced bySaccharopolyspora pagona, which may be used in the compositions of theinvention, may be produced via fermentation by conventional techniquesknown in the art. Other spinosyn compounds that may be used in thecompositions of the invention are disclosed in U.S. Pat. Nos. 5,496,931;5,670,364; 5,591,606; 5,571,901; 5,202,242; 5,767,253; 5,840,861;5,670,486; 5,631,155 and 6,001,981, all incorporated by reference hereinin their entirety. The spinosyn compounds may include, but are notlimited to, spinosyn A, spinosyn D, spinosad, spinetoram, orcombinations thereof. Spinosad is a combination of spinosyn A andspinosyn D, and spinetoram is a combination of 3′-ethoxy-5,6-dihydrospinosyn J and 3′-ethoxy spinosyn L.

In general, the additional active agent is included in the extendedrelease formulations of the present invention in an amount of betweenabout 0.1 μg and about 1000 mg. More typically, the additional activeagent may be included in an amount of about 10 μg to about 500 mg, about1 mg to about 300 mg, about 10 mg to about 200 mg or about 10 mg toabout 100 mg.

In other embodiments of the invention, the additional active agent maybe included in the composition to deliver a dose of about 5 μg/kg toabout 50 mg/kg per weight of the animal. In other embodiments, theadditional active agent may be present in an amount sufficient todeliver a dose of about 0.01 mg/kg to about 30 mg/kg, about 0.1 mg/kg toabout 20 mg/kg, or about 0.1 mg/kg to about 10 mg/kg of weight ofanimal. In other embodiments, the additional active agent may be presentin a dose of about 5 μg/kg to about 200 μg/kg or about 0.1 mg/kg toabout 1 mg/kg of weight of animal. In still another embodiment of theinvention, the additional active agent is included in a dose betweenabout 0.5 mg/kg to about 50 mg/kg.

In one embodiment, the extended release injectable formulations of thepresent invention, which include at least an isoxazoline active agent, apharmaceutically acceptable polymer and a solvent, have beensurprisingly discovered to be stable and effective against a broadspectrum of ectoparasites, and possibly also endoparasites if anotheractive is included, for an extended period of time; e.g., a period fromthree (3) up to twelve (12) months or longer, while exhibiting favorableproperties with respect to the site of injection.

Dosage forms may contain from about 0.5 mg to about 5 g of a combinationof active agents. More typically, the amount of active agent(s) in thecompositions of the invention will be from about 1 mg to about 3 g. Inanother embodiment, the amount of active agent(s) in the compositionswill be from about 20 mg to about 3 g. In another embodiment, the amountof active agent(s) present in the compositions will be from about 20 mgto about 2 g, about 20 mg to about 1.5 g or about 20 mg to about 1 g. Inother embodiments, the amount of active agent(s) in the compositionswill be from about 20 mg to about 500 mg, about 30 mg to about 200 mg orabout 50 mg to about 200 mg. In still another embodiment, the amount ofactive agent(s) present in the compositions will be from about 50 mg toabout 2 g, about 50 mg to about 1 g or about 50 mg to about 500 mg. Inyet another embodiment of the invention, the about of active agent(s)present will be from about 100 mg to about 2 g, about 100 mg to about 1g or about 100 mg to about 500 mg.

In another embodiment, the amount of active agent(s) present in anamount of from about 1 mg to about 500 mg of an active agent, about 1 mgto about 100 mg or about 1 mg to about 25 mg. In still otherembodiments, the amount of the active agent present in the compositionsis about 10 mg about 50 mg or about 10 mg to about 100 mg. In otherembodiments, the amount of active agent present in the compositions isabout 50 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mgto about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 600mg, about 400 mg to about 800 mg, or about 500 mg to about 1000 mg.

The compositions of the invention are made by mixing the appropriateamount of the active agents, pharmaceutically acceptable polymer, asolvent and, optionally, an antioxidant, pharmaceutically acceptableadditive and/or excipient to form a formulation of the invention. Insome embodiments the formulations of the present invention can beobtained by following the method of making these forms described aboveby the description of making these forms found in general formulationtext known to those in the art, e.g. Remington—The Science and Practiceof Pharmacy (21^(st) Edition) (2005), Goodman & Gilman's ThePharmacological Basis of Therapeutics (11^(th) Edition) (2005) andAnsel's Pharmaceutical Dosage Forms and Drug Delivery Systems (8^(th)Edition), edited by Allen et al., Lippincott Williams & Wilkins, (2005).

Methods of Treatment

In another aspect of the invention, a method for preventing or treatinga parasite infestation/infection in an animal is provided, comprisingadministering to the animal an extended release injectable formulationcomprising an effective amount of at least one isoxazoline compound, apharmaceutically acceptable polymer and a solvent. The formulations ofthe invention have long-lasting efficacy against ectoparasites (e.g.fleas and ticks) and in certain embodiments in which the compositionsinclude an additional active agent they may also be active againstendoparasites that harm animals.

In one embodiment of the invention, methods for the treatment orprevention of a parasitic infestation or infection in a domestic animalare provided, which comprise administering an extended releaseinjectable formulation comprising an effective amount of at least oneisoxazoline active agent to the animal. Ectoparasites against which themethods and compositions of the invention are effective include, but arenot limited to, fleas, ticks, mites, mosquitoes, flies and lice. Incertain embodiments wherein the inventive formulations include one ormore additional active agents that are active against internal parasitesthe compositions and methods of the invention may also be effectiveagainst endoparasites including, but not limited to, cestodes,nematodes, hookworms and roundworms of the digestive tract of animalsand humans.

In one embodiment for treatment against ectoparasites, the ectoparasiteis one or more insect or arachnid including those of the generaCtenocephalides, Rhipicephalus, Dermacentor, Ixodes, Amblyomma,Haemaphysalis, Hyalomma, Sarcoptes, Psoroptes, Otodectes, Chorioptes,Hypoderma, Damalinia, Linognathus, Haematopinus, Solenoptes,Trichodectes, and Felicola.

In another embodiment for the treatment against ectoparasites, theectoparasite is from the genera Ctenocephalides, Rhipicephalus,Dermacentor and/or Ixodes. The ectoparasites treated include but are notlimited to fleas, ticks, mites, mosquitoes, flies, lice, blowfly andcombinations thereof. Specific examples include, but are not limited to,cat and dog fleas (Ctenocephalides sp. such as Ctenocephalides felis,Ctenocephalides canis, and the like), ticks (Rhipicephalus sp., Ixodessp., Dermacentor sp., Amblyomma sp. and the like), and mites (Demodexsp., Sarcoptes sp., Otodectes sp. and the like), lice (Trichodectes sp.,Cheyletiella sp., Linognathus sp., and the like), mosquitoes (Aedes sp.,Culex sp., Anopheles sp., and the like) and flies (Haematobia sp.including Haematobia irritans, Musca sp., Stomoxys sp. includingStomoxys calcitrans, Dermatobia sp., Cochliomyia sp., and the like).

Additional examples of ectoparasites include but are not limited to thetick genus Rhipicephalus, especially those of the species microplus(cattle tick), decoloratus and annulatus; myiasis such as Dermatobiahominis (known as Berne in Brazil) and Cochliomyia hominivorax(greenbottle); sheep myiasis such as Lucilia sericata, Lucilia cuprina(known as blowfly strike in Australia, New Zealand and South Africa).Flies proper, namely those whose adult constitutes the parasite, such asHaematobia irritans (horn fly) and Stomoxys calcitrans (stable fly);lice such as Linognathus vituli, etc.; and mites such as Sarcoptesscabiei and Psoroptes ovis. The above list is not exhaustive and otherectoparasites are well known in the art to be harmful to animals andhumans. These include, for example migrating dipterous larvae.

In some embodiments of the invention, the composition can also be usedto treat against endoparasites such as those helminths selected from thegroup consisting of Anaplocephala, Ancylostoma, Necator, Ascaris,Capillaria, Cooperia, Dipylidium, Dirofilaria, Echinococcus, Enterobius,Fasciola, Haemonchus, Oesophagostomum, Ostertagia, Toxocara,Strongyloides, Toxascaris, Trichinella, Trichuris, Angiostrongylus andTrichostrongylus, among others.

In one embodiment, the invention provides methods for the treatment andprevention of parasitic infections and infestations of animals (eitherwild or domesticated), including livestock and companion animals such ascats, dogs, horses, birds including chickens, sheep, goats, pigs, deer,turkeys and cattle, with the aim of ridding these hosts of parasitescommonly encountered by such animals.

In an embodiment, the invention provides methods and compositions forthe treatment or prevention of parasitic infections and infestations incompanion animals including, but not limited to, cats and dogs. Themethods and compositions are particularly effective for preventing ortreating parasitic infestations of cats and dogs with fleas and ticks.

In another embodiment, the methods and compositions of the invention areused for the treatment or prevention of parasitic infections andinfestations in cattle or sheep. When treating livestock animals such ascattle or sheep, the methods and compositions are particularly effectiveagainst Rhipicephalus (formerly Boophilus) microplus, Haematobiairritans (horn fly), Stomoxys calcitrans (stable fly), and sheep myiasissuch as Lucilia sericata, Lucilia cuprina (known as blowfly strike inAustralia, New Zealand and South Africa).

The terms “treating” or “treat” or “treatment” are intended to mean theadministration of an extended release formulation of the presentinvention to an animal that has a parasitic infestation for theeradication of the parasite or the reduction of the number of theparasites infesting the animal undergoing treatment. It is noted thatthe compositions of the invention may be used to prevent such aparasitic infestation.

The terms “prevent”, “prevention” or “prophylaxis” are intended to meanthe administration of the extended release formulations of the presentinvention to the animal before the parasitic infection or infestationhas occurred in order to keep said infection or infestation fromoccurring.

The formulations of the invention are administered in parasiticidallyeffective amounts which are which are suitable to control the parasitein question to the desired extent, as described below. In each aspect ofthe invention, the compounds and compositions of the invention can beapplied against a single pest or combinations thereof.

By “antiparasitic effective amount” is intended a sufficient amount of acomposition of the invention to eradicate or reduce the number ofparasites infesting the animal. In some embodiments, an effective amountof the active agent achieves at least 70% efficacy (% reduction vs.control) against the target parasite. In other embodiments, an effectiveamount of the active agent achieves at least 80%, or at least 90%efficacy against the target pests. Preferably, an effective amount ofthe active agent will achieve at least 95%, at least 98% or 100%efficacy against the target parasites.

Generally, a dose of from about 0.001 to about 100 mg per kg of bodyweight given as a single dose or in divided doses for a period of from 1to 5 days will be satisfactory but, of course, there can be instanceswhere higher or lower dosage ranges are indicated, and such are withinthe scope of this invention. It is well within the routine skill of thepractitioner to determine a particular dosing regimen for a specifichost and parasite.

In some embodiments for companion animals, the dose of the isoxazolineactive agent administered from the extended release injectableformulations of the invention is between about 0.1 to about 50 mg per kgof body weight. More typically the dose of the isoxazoline active agentadministered is about 0.5 to about 40 mg/kg or about 0.5 to about 30mg/kg body weight. In another embodiment, the dose of the isoxazolineactive agent administered is about 10 to about 40 mg/kg, about 15 toabout 35 mg/kg or about 20 to about 30 mg/kg of body weight. In anotherembodiment, the dose of the isoxazoline active agent will be about 20 toabout 25 mg/kg of body weight.

In other embodiments, the dose administered may be lower depending onthe animal and the isoxazoline administered. For example, if thecomposition comprises the more active enantiomer of the isoxazolinecompounds a lower dose may be administered. In some embodiments, thedose is from about 0.1 to about 30 mg/kg of body weight. In anotherembodiment, the dose may be from about 0.1 to about 20 mg/kg or about0.1 to about 10 mg/kg of body weight. In other embodiments, the dose maybe from about 1 to about 20 mg/kg of body weight or about 1 to about 10mg/kg. In yet another embodiment, the dose may be from about 5 to about20 mg/kg or about 10 to about 20 mg/kg of body weight. In anotherembodiment, the dose may be from about 10 to about 30 mg/kg of bodyweight.

In other embodiments for the treatment of livestock animals such ascattle or sheep, doses of the isoxazoline active agent administered maybe about 0.1 to about 40 mg/kg of body weight. More typically the dosesadministered will be about 1 to about 30 mg/kg, about 1 to about 20mg/kg or about 1 to about 10 mg/kg of bodyweight. In yet anotherembodiment, the dose may be from about 10 to about 25 mg/kg, about 15 toabout 30 mg/kg of body weight or about 20 to about 30 mg/kg of bodyweight.

In one embodiment of the method of use in dogs or cats, the extendedrelease formulations of the present invention comprising an isoxazolinecompound has an efficacy against fleas and/or ticks of at least about90.0% or higher for about 3 months, or longer. In another embodiment,the extended release formulations of the present invention provide anefficacy against fleas and/or ticks of at least 95.0% or higher forabout, 3 months or longer. In yet another embodiment, the extendedrelease formulations of the invention provide an efficacy against fleasand/or ticks of at least 90% or higher for about 6 months or longer. Inyet another embodiment, the extended release formulations of theinvention provide an efficacy against fleas and/or ticks of at least 95%or higher for about 6 months or longer. In another embodiment, theextended release formulations of the invention provide an efficacyagainst fleas and/or ticks of at least 90% or higher for about 9 monthsor longer. In yet another embodiment, the extended release formulationsof the invention provide an efficacy against fleas and/or ticks of atleast 90% or higher for about 12 months or longer. In anotherembodiment, the extended release formulations of the present inventionprovide an efficacy against fleas and/or ticks in cats and dogs of atleast about 90% for two months, or longer. In another embodiment, theextended release formulations of the present invention efficacy againstfleas and/or ticks in cats and dogs of about 95% for about 3 months, orlonger. In still another embodiment, the compositions provide anefficacy of about 95% for about 5 months or longer.

In another aspect of the invention, a kit for the treatment orprevention of a parasitic infestation in an animal is provided, whichcomprises an extended release formulation of the invention and a syringeor dosing device.

EXAMPLES

The invention is further described by the following non-limitingexamples which further illustrate the invention, and are not intended,nor should they be interpreted to, limit the scope of the invention.

Formulation Examples

The following extended release injectable formulations were prepared bymixing the following ingredients. Unless indicated otherwise, theconcentrations of each component is percent (%) weight per weight (w/w)and MW refers to weight average molecular weight.

Example 1

Compound of formula (IIc)   26% Medium molecular weight (MMW) PLGA(50:50)   1% Propylene carbonate 50.9% Triacetin 22.2% BHT 0.02%.

Example 2

Compound of formula (IIc)   26% Low molecular weight (LMW) PLGA (50:50)  5% Propylene carbonate 48.0% Triacetin 21.0% BHT 0.02%.

Example 3

Compound of formula (IIc)   26% MMW PLGA (50:50)   5% Propylenecarbonate 48.0% Triacetin 21.0% BHT 0.02%.

Example 4

Compound of formula (IIc)   20% MMW PLGA (50:50)   3% Propylenecarbonate 53.9% Triacetin 23.1% BHT 0.02%.

Example 5

Compound of formula (IIc)   26% MMW PLGA (50:50)   3% Propylenecarbonate 49.7% Triacetin 21.3% BHT 0.02%.

Example 6

Compound of formula (IIc)   20% LMW PLGA (50:50)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 7

Compound of formula (S)-IIc   20% MMW PLGA (50:50)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 8

Compound of formula (S)-IIc   10% LMW PLGA (50:50)   5% Propylenecarbonate 59.5% Triacetin 25.5% BHT 0.02%.

Example 9

Compound of formula (S)-IIc   10% LMW PLGA (50:50)  2.5% Propylenecarbonate 61.25% Triacetin 26.25% BHT  0.02%.

Example 10

Compound of formula (IIc)   20% LMW PLGA (50:50)   7% Propylenecarbonate 51.1% Triacetin 21.9% BHT 0.02%.

Example 11

Compound of formula (IIc)   20% MMW PLGA (50:50)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 12

Compound of formula (IIc)   20% High molecular weight (HMW) PLGA (75:25)  5% Propylene carbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 13

Compound of formula (IIc)   15% HMW PLGA (75:25)   5% Propylenecarbonate   56% Triacetin   24% BHT 0.02%.

Example 14

Compound of formula (IIc)   20% LMW PLGA (50:50)   5% Propylenecarbonate   75% BHT 0.02%.

Example 15

Compound of formula (IIc)   20% LMW PLGA (50:50)   5% Propylenecarbonate   73% Poloxamer 124   2% BHT 0.02%.

Example 16

Compound of formula (IIc)   20% LMW PLGA (50:50)   5% Propylenecarbonate   55% Poloxamer 124   20% BHT 0.02%.

Example 17

Compound of formula (IIc)   20% HMW PLGA (50:50)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 18

Compound of formula (IIc)   20% HMW PLGA (50:50)   5% Propylenecarbonate 51.1% Triacetin 21.9% Poloxamer 124   2% BHT 0.02%.

Example 19

Compound of formula (IIc) 12.5% HMW PLGA (75:25) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 20

Compound of formula (S)-IIc 12.5% HMW PLGA (75:25) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 21

Compound of formula (IIc) 12.5% HMW PLGA (75:25) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 22

Compound of formula (IIc) 12.5% HMW PLGA (75:25)   20% Propylenecarbonate 47.5% Triacetin 20.3% BHT 0.02%.

Example 23

Compound of formula (IIc) 12.5% HMW PLGA (75:25)   15% Propylenecarbonate 50.7% Triacetin 21.8% BHT 0.02%.

Example 24

Compound of formula (IIc) 12.5% HMW PLGA (75:25) 12.5% Propylenecarbonate 51.1% Triacetin 21.9% Poloxamer 124   2% BHT 0.02%.

Example 25

Compound of formula (IIc) 12.5% LMW PLGA (75:25) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Example 26

Compound of formula (IIc) 12.5% LMW PLGA (50:50) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%.

Efficacy Examples

The following examples demonstrate the efficacy of the extended releaseinjectable compositions of the invention against ectoparasites incompanion and farm animals.

Example 27

A study was conducted to determine the level of isoxazoline compound(IIc) in the plasma of dogs over time after a single subcutaneousinjection of the extended release formulations of the invention.Accordingly, the extended release formulations of Examples 1, 2 and 3were administered to dogs at a dose of at 25 mg/kg once at Day 0. Theconcentration of compound (IIc) in the plasma was measuredintermittently to determine if the concentration of the compound wassufficient to control fleas. The concentration of compound (IIc) in thebloodstream has been strongly correlated with efficacy against fleas(see, for example, Letendre et al., Veterinary Parasitology 201 (2014)190-197). Thus, the concentration of about 20 ng/ml of compound (IIc) isknown to effectively control fleas on dogs (EC₉₀ 23 ng/ml). In thestudy, the concentration of compound (IIc) was found to be above 20ng/ml for at least 180 days post treatment. Accordingly, the extendedrelease formulations of Examples 1, 2 and 3 would be expected to behighly efficacious to control fleas in dogs for at least 180 days.

Example 28

In another study, the concentration of isoxazoline compound (IIc) in theplasma of dogs was measured after a single subcutaneous injection of theextended release formulations of Examples 4 and 5. The concentration ofcompound (IIc) was found to be above about 20 ng/ml for at least about 5months (154 days) after treatment. Thus, the extended releaseformulations of Examples 4 and 5 would be expected to be highlyefficacious against fleas on dogs for at least about five months.

Example 29

In separate study, the concentration of isoxazoline compound (IIc) inthe plasma of dogs was measured after a single subcutaneous injection ofthe extended release formulations of Examples 4 and 5. The concentrationof compound (IIc) was found to be above about 20 ng/ml for greater thanseven months (238 days) after treatment.

Example 30

Compound of formula (IIc)   26% PLGA (50:50) (MW~52 kDa)    1% Propylenecarbonate 22.16% Triacetin  50.8% BHT  0.02%

Example 31

Compound of formula (IIc)   26% PLGA (50:50) (MW~9 kDa)    5% Propylenecarbonate 20.95% Triacetin 48.03 BHT  0.02%

Example 32

Compound of formula (IIc)   26% PLGA (50:50) (MW~52 kDa)    5% Propylenecarbonate 20.95% Triacetin 48.03 BHT  0.02%

Example 33

Compound of formula (IIc)   20% PLGA (70:30) (MW~52 kDa)    3% Propylenecarbonate 53.89% Triacetin 23.09% BHT  0.02%

Example 34

Compound of formula (IIc)   26% PLGA (70:30) (MW~52 kDa)    3% Propylenecarbonate 49.69% Triacetin 21.29% BHT  0.02%

Example 35

Compound of formula (IIc)   20% PLGA (50:50) (MW~09)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 36

Compound of formula (S)-IIc   20% PLGA (50:50) (MW~9)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 37

Compound of formula (S)-IIc   10% PLGA (50:50) (MW~9)   5% Propylenecarbonate 59.5% Triacetin 25.5% BHT 0.02%

Example 38

Compound of formula (S)-IIc   10% PLGA (50:50) (MW~9)  2.5% Propylenecarbonate 61.25% Triacetin 26.25% BHT  0.02%

Example 39

Compound of formula (IIc)   20% PLGA (50:50) (MW~9)   7% Propylenecarbonate 51.1% Triacetin 21.9% BHT 0.02%

Example 40

Compound of formula (IIc)   20% PLGA (50:50) (MW~52)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 41

Compound of formula (IIc)   20% PLGA (75:25) (MW~111-115)   5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 42

Compound of formula (IIc)   15% PLGA (75:25) (MW~111-115)   5% Propylenecarbonate   56% Triacetin   24% BHT 0.02%

Example 43

Compound of formula (IIc)   20% PLGA (50:50) (MW~9)   5% Propylenecarbonate   75% BHT 0.02%

Example 44

Compound of formula (IIc)   20% PLGA (50:50) (MW~9)   5% Propylenecarbonate   73% Poloxamer 124   2% BHT 0.02%

Example 45

Compound of formula (IIc)   20% PLGA (50:50) (MW~9)   5% Propylenecarbonate   55% Poloxamer 124   20% BHT 0.02%

Example 46

Compound of formula (IIc) 12.5% PLGA (75:25) (MW~111-115) 12.5%Propylene carbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 47

Compound of formula (IIc) 12.5% PLGA (75:25) (MW~111-115)   20%Propylene carbonate 47.7% Triacetin 20.3% BHT 0.02%

Example 48

Compound of formula (IIc) 12.5% PLGA (75:25) (MW~111-115)   15%Propylene carbonate 50.7% Triacetin 21.8% BHT 0.02%

Example 49

Compound of formula (IIc) 12.5% PLGA (75:25) (MW~111-115) 12.5%Propylene carbonate 51.1% Triacetin 21.9% Poloxamer 124   2% BHT 0.02%

Example 50

Compound of formula (IIc) 12.5% PLGA (75:25) (MW~9) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 51

Compound of formula (IIc) 12.5% PLGA (50:50) (MW~9) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 52

Compound of formula (S)-IIc 12.5% PLGA (75:25) (MW~111-115) 12.5%Propylene carbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 53

Compound of formula (IIc) 12.5% PLGA (50:50) (MW~9) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 54

Compound of formula (S)-IIc 12.5% PLGA (50:50) (MW~9) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 55

Compound of formula (S)-IIc 12.5% PLGA (50:50) (MW~52) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 56

Compound of formula (S)-IIc 12.5% PLGA (50:50) (MW~111-115) 12.5%Propylene carbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 57

Compound of formula (S)-IIc 12.5% PLGA (50:50) (MW~9) 12.5% Propylenecarbonate 51.1% Triacetin 21.9% Poloxamer-124   2% BHT 0.02%

Example 58

Compound of formula (S)-IIc 12.5% PLGA (75:25) (MW~9)   15% Propylenecarbonate 50.7% Triacetin 21.8% BHT 0.02%

Example 59

Compound of formula (S)-IIc 12.5% PLGA (75:25) (MW~9) 12.5% Propylenecarbonate 52.5% Triacetin 22.5% BHT 0.02%

Example 60

Compound of formula (S)-IIc 12.5% PLGA (50:50) (MW 9) 12.5% Propylenecarbonate 63.7% Triacetin 11.3% BHT 0.02%

Example 61

Compound of formula (S)-IIc  12.5% PLGA (50:50) (MW~52)  12.5% Propylenecarbonate  51.1% Triacetin  21.9% Poloxamer-124    2% BHT  0.02%

Example 62

Compound of formula (IIc)   26% PLGA (50:50) (MW~52)    1% Propylenecarbonate 50.82% Triacetin  22.2% BHT  0.02%

Example 63

Compound of formula (IIc)   26% PLGA (50:50) (MW 9)    5% Propylenecarbonate 48.03% Triacetin 20.95% BHT  0.02%

Example 64

Compound of formula (IIc)   26% PLGA (50:50) (MW~52)    5% Propylenecarbonate 48.03% Triacetin 20.95%

Efficacy Example Example 65

The following example demonstrates the efficacy of the long-actinginjectable compositions of the invention against ectoparasites incompanion animals (dogs).

The compositions for the following Treatment Groups in Table 1 wereprepared. Except for the dose, all values in the table are % (w/w):

TABLE 1 PLGA PLGA Compound of (75:25) (75:25) Dose Group Formula (S)-IIc(MW ~9)¹ (MW ~52)¹ PC² Triacetin P-124³ BHT (mg/kg) 1 — — 12.5 61.2126.27 — 0.02 N/A 2 12.5 — 12.5 51.05 21.92 2 0.02 12.5 3 12.5 — 12.552.46 22.52 — 0.02 12.5 4 12.5 — 15 49.31 21.17 2 0.02 12.5 5 12.5 15 —50.71 21.77 — 0.02 12.5 6 12.5 — 12.5 51.06 21.92 2 0.02 6.25 ¹Weightaverage molecular weight (kDa) ²Propylene carbonate

³ Poloxamer 124

Thirty beagles were studied to determine the effectiveness of theinventive extended release injectable compositions (compositions ofTreatment Groups 2-6 above) against fleas (Ctenocephalides felis) for atleast 180 days after treatment.

Six treatment groups of five dogs each were formed, each treatment groupreceived one injection of the extended release formulation identifiedabove (Group 1 being the control). All dogs were injected one at day 0.Each animal was infested with C. felis on Day 6, 34, 69 and 111. Fleaswere counted upon removal on Days 7, 35, 70 and 112. Fleas were alsocounted for Groups 5 and 6 on Day 190. Percent reduction (also referredas efficacy) against fleas was 100% for all treatment Groups (i.e.,Groups 2-6) through Day 112. Percent reduction on Day 190 against fleaswas 96.9% for Group 5 and 100.0% for Group 6.

Blood Plasma Levels

Further, the plasma concentrations of the isoxazoline compound offormula (S)-IIc was determined by collecting a single blood samples foreach of the animals as specific time points after the singlesubcutaneous rejection of the extended release compositions identifiedabove.

The concentration of the compound of formula (S)-IIc was found to beabove 50 ng/ml 183 days after treatment, thereby indicating that thecompositions of Treatment Groups 2-6 would be effective against fleasand ticks.

The invention is further described by the following numbered paragraphs:

#1. An extended release injectable composition for the treatment orprevention of parasite infections or infestations in an animalcomprising an antiparasitic effective amount of at least one isoxazolineactive agent, a pharmaceutically acceptable polymer and a solvent ormixture of solvents.

#2 The extended release injectable composition according to paragraph #1comprising:

a) an antiparasitic effective amount of at least one isoxazoline activeagent, which is:

-   -   i) an isoxazoline compound of formula (I):

wherein:

-   -   B¹, B² and B³ are each independently C—R or N;    -   each R is independently H, halogen, cyano, —NO₂, alkyl,        haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio,        alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,        haloalkylsulfonyl, alkylamino, dialkylamino or alkoxycarbonyl;    -   R¹ is C₁-C₃alkyl or C₁-C₃haloalkyl;    -   Y is an optionally substituted phenylene, naphthylene,        indanylene, a 5- or 6-membered heteroarylene or an 8-10-membered        fused heterobicyclylene, wherein the optional substituents are        selected from the group consisting of halogen, alkyl, haloalkyl,        cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, alkylthio,        haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,        haloalkylsulfonyl, alkylamino, dialkylamino, —CN or —NO₂ and        NH₂—C(═S)—;    -   Q is X—NR²R³, the group (—CH₂—)(—CH₂—)N—R³, OH, NH₂, alkoxy,        haloalkoxy, alkylamino, haloalkylamino, dialkylamino,        halodialkylamino, thiol, alkylthio, haloalkylthio,        alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,        haloalkylsulfonyl, or an optionally substituted 5- or 6-membered        carbocyclyl, heterocyclyl or heteroaryl ring;    -   X is (CH₂)_(n), CH(CH₃), CH(CN), C(═O) or C(═S);    -   R² is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl,        cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;    -   R³ is H, OR⁷, NR⁸R⁹ or Q¹; or alkyl, haloalkyl, alkenyl,        haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl,        cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,        alkylaminocarbonyl or dialkylaminocarbonyl, each optionally        substituted with one or more substituents independently selected        from R⁴; or

R² and R³ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of alkyl, halogen, —CN, —NO₂ andalkoxy;

each R⁴ is independently halogen; alkyl, cycloalkyl, alkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkylamino, haloalkylamino, dialkylamino,dihaloalkylamino, cycloalkylamino, alkylcarbonyl, alkoxycarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, haloalkylcarbonyl,haloalkoxycarbonyl, haloalkylaminocarbonyl, dihaloalkylaminocarbonyl,hydroxy, —NH₂, —CN or —NO₂; or Q²;

each R⁵ is independently halogen, alkoxy, haloalkoxy, alkylthio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, alkylamino, dialkylamino, alkoxycarbonyl, —CN or—NO₂;

each R⁶ is independently halogen, alkyl, haloalkyl, cycloalkyl,halocycloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkylamino, dialkylamino, —CN, —NO₂, phenyl or pyridinyl;

R⁷ is H; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each optionally substituted with one of more halogen;

R⁸ is H, alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl,cycloalkylalkyl, alkylcarbonyl or alkoxycarbonyl;

R⁹ is H; Q³; or alkyl, alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁴; or

R⁸ and R⁹ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of alkyl, halogen, —CN, —NO₂ andalkoxy;

Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-or 10-membered fused bicyclic ring system optionally containing one tothree heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, eachring or ring system optionally substituted with one or more substituentsindependently selected from R⁵;

Q² is independently a phenyl ring or a 5- or 6-membered heterocyclicring, each ring optionally substituted with one or more substituentsindependently selected from R⁶;

Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ringoptionally substituted with one or more substituents independentlyselected from R⁶; and

n is 0, 1 or 2; and/or

-   -   ii) an isoxazoline compound of formula (II):

wherein:

A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from the groupconsisting of CR³ and N, provided that at most 3 of A¹, A², A³, A⁴, A⁵and A⁶ are N;

B¹, B² and B³ are independently selected from the group consisting ofCR² and N;

W is O or S;

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, each optionally substitutedwith one or more substituents independently selected from R⁶;

each R² is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂;

each R³ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN or —NO₂;

R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl;

R⁵ is H, OR¹⁰, NR¹¹R¹² or Q¹; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁷; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂ alkoxy;

each R⁶ is independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, —CN or —NO₂;

each R⁷ is independently halogen; C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₂-C₇alkylcarbonyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉dialkylaminocarbonyl, C₂-C₇ haloalkylcarbonyl, C₂-C₇ haloalkoxycarbonyl,C₂-C₇ haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl, hydroxy,—NH₂, —CN or —NO₂; or Q²;

each R⁸ is independently halogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, C₂-C₄ alkoxycarbonyl, —CN or —NO₂;

each R⁹ is independently halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN, —NO₂, phenyl or pyridinyl;

R¹⁰ is H; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one of more halogen;

R¹¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl;

R¹² is H; Q³; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one or more substituents independentlyselected from R⁷; or

R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂ alkoxy;

Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-or 10-membered fused bicyclic ring system optionally containing one tothree heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, eachring or ring system optionally substituted with one or more substituentsindependently selected from R⁸;

each Q² is independently a phenyl ring or a 5- or 6-memberedheterocyclic ring, each ring optionally substituted with one or moresubstituents independently selected from R⁹;

Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ringoptionally substituted with one or more substituents independentlyselected from R⁹; and

n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

-   -   iii) an isoxazoline compound of formula (III):

wherein:

R₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachwhich is unsubstituted or substituted with one or more of halogen,hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—,R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

X is aryl or heteroaryl, which may be unsubstituted or substituted byone or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

A₁ is oxygen; and

A₂ is oxygen, NR₂ or CR₇R₈;

G is G-1 or G-2;

B₁, B₂, B₃, B₄ and B₅ are independently N or C—R₉;

Y is hydrogen, halogen, —CN; or Y is alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl,cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which isunsubstituted or substituted with one or more of halogen, hydroxy,amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—,R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6,Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;

R₂, R₃ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, R₁₀S(O)—, R₁₀S(O)₂—, R₁₀C(O)—,R₁₀C(S)—, R₁₀R₁₁NC(O)—, R₁₀R₁₁NC(S)—R₁₀OC(O)—;

R₄, R₅ and R₆ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, aryl or heteroaryl;

R₇ and R₈ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynylor haloalkynyl;

R₉ is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each which is unsubstituted or substituted with one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

R₁₀, R₁₁, R₁₂ and R₁₃ are each independently hydrogen, alkyl, haloalkyl,thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,haloalkenyl, alkynyl or haloalkynyl; or

R₁₀ together with R₁₁ form ═O, ═S or ═NR₂; or

R₁₂ together with R₁₃ form ═O, ═S or ═NR₂;

W is O, S or NR₂,

n is 1-4; and

m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or

-   -   iv) an isoxazoline compound of formula (IV)

wherein X¹, X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof; and/or

-   -   iv) an isoxazoline compound of formula (V)

wherein X¹, X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof; and/or

-   -   v) an isoxazoline compound of formula (V):

wherein R¹, R² and R are independently H, Cl, F or CF₃;

Y is the diradical group

and

T is a C₁-C₆-alkyl group which is unsubstituted or substituted byhalogen, cyano, nitro, amino, hydroxyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-alkylthio, carboxy, carbamoyl or C₂-C₆-alkanoylgroup which may be unsubstituted or substituted in the alkyl portion byhalogen or a pharmaceutical acceptable salt thereof; and/or

-   -   vi) an isoxazoline compound of formula (VI):

wherein Y is hydrogen, fluoro, chloro or bromo;

-   -   R¹ is phenyl substituted with 2-4 substituents selected from        halogen, methyl, difluoromethyl, trifluoromethyl, methoxy,        trifluoromethoxy or trifluoroethoxy;    -   R² is methyl, fluoromethyl, trifluoromethyl or perfluoroethyl;    -   R^(3a) and R^(3b) are independently selected from hydrogen,        methyl, ethyl or fluoromethyl; or R^(3a) and R^(3b) together        combine with the carbon to which they are attached to form a        cyclopentyl ring or a cyclohexyl ring; or a pharmaceutically        acceptable salt thereof;

b) at least one pharmaceutically acceptable polymer;

c) at least one solvent or a mixture of solvents;

d) optionally, an antioxidant; and

e) optionally at least one pharmaceutically acceptable additive,excipient or mixtures thereof.

#3. The extended release injectable composition according to paragraph#2, wherein the isoxazoline active agent is a compound of formula (II).

#4. The extended release injectable composition according to paragraph#3, wherein in the isoxazoline active agent is a compound of the formula(II):

or a pharmaceutically acceptable salt thereof,

wherein:

R² independently is halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl

R⁴ is H or C₁-C₆ alkyl;

R⁵ is C₁-C₄ alkyl optionally substituted with one or more R⁷; and R⁷ isC₂-C₇ alkylcarbonyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl,C₃-C₉ dialkylaminocarbonyl, C₂-C₇ haloalkylcarbonyl, C₂-C₇haloalkoxycarbonyl, C₂-C₇ haloalkylaminocarbonyl, C₃-C₉dihaloalkylaminocarbonyl; and

n is 0, 1 or 2.

#5. The extended release injectable composition according to paragraph#4, wherein in the isoxazoline active agent is a compound of formula(IIc), (IId), (IIe) or (IIf):

or a pharmaceutically acceptable salt thereof.

#6. The extended release injectable composition according to paragraph#1 or paragraph #2, wherein the isoxazoline active agent is enriched inan enantiomer.

#7. The extended release injectable composition according to paragraph#6, wherein in the isoxazoline active agent is a compound of formula(S)-IIc, (S)-IId, (S)-IIe or (S)-IIf:

-   -   or a pharmaceutically acceptable salt thereof.

#8. The extended release injectable composition according to paragraph#2, wherein the isoxazoline active agent is a compound of formula (III):

wherein:

R₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachwhich is unsubstituted or substituted with one or more of halogen,hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—,R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

X is aryl or heteroaryl, which may be unsubstituted or substituted byone or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

A₁ is oxygen; and

A₂ is oxygen, NR₂ or CR₇R₈;

G is G-1 or G-2;

B₁, B₂, B₃, B₄ and B₅ are independently N or C—R₉;

Y is hydrogen, halogen, —CN; or Y is alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, alkylcycloalkyl,cycloalkylalkyl, aryl, or heterocyclyl or heteroaryl each of which isunsubstituted or substituted with one or more of halogen, hydroxy,amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—,R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6,Y-7, Y-8, Y-9, Y-10, Y-11, Y-12 or Y-13;

R₂, R₃ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, R₁₀S(O)—, R₁₀S(O)₂—, R₁₀C(O)—,R₁₀C(S)—, R₁₀R₁₁NC(O)—, R₁₀R₁₁NC(S)—R₁₀OC(O)—; R₄, R₅ and R₆ areindependently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, aryl or heteroaryl;

R₇ and R₈ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynylor haloalkynyl;

R₉ is hydrogen, halogen, —CN, or alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each which is unsubstituted or substituted with one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂;

R₁₀, R₁₁, R₁₂ and R₁₃ are each independently hydrogen, alkyl, haloalkyl,thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl,haloalkenyl, alkynyl or haloalkynyl; or

R₁₀ together with R₁₁ form ═0, ═S or ═NR₂; or

R₁₂ together with R₁₃ form ═O, ═S or ═NR₂;

W is O, S or NR₂;

n is 1-4; and

m is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.

#9. The extended release injectable composition according to paragraph#8 wherein isoxazoline agent is a compound of formulae III-1.001 toIII-1.025 or III-2.00-III-2.018:

Compounds III-1.001 to III-1.025 Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵R¹⁶ 1.001 3,5-Cl₂ C—H C—H C—H C—H N H CH₂C(O)NHCH₂CF₃ 1.002 3,5-Cl₂ C—HC—H C—H C—H N H CH₂CF₃ 1.003 3,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂CO₂CH₃1.004 3,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂CO₂H 1.005 3,5-(CF₃)₂ C—H C—HC—H C—H N CH₃ CH₂C(O)NHCH₂CF₃ 1.006 3,5-(CF₃)₂ C—H C—H C—H C—H N HCH₂C(O)NHCH₂CF₃ 1.007 3,5-(CF₃)₂ C—H C—H C—H C—H N H CH₂CH₂SCH₃ 1.0083,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.009 3,5-(CF₃)₂ C—HC—H C—H C—H C—H H CH₂CH₂SCH₃ 1.010 3,5-(CF₃)₂ C—H C—H C—H C—H C—H HCH₂CF₃ 1.011 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.012 3,5-Cl₂C—H C—H C—H C—H C—H H CH₂CF₃ 1.013 3,5-Cl₂ C—H C—H C—H C—H C—H HCH₂CH₂SCH₃ 1.014 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.0153-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CF₃ 1.016 3-Cl, 5-CF₃ C—H C—H C—HC—H C—H H CH₂CH₂SCH₃ 1.017 3,5-Cl₂ C—H C—H C—Me C—H C—Me HCH₂C(O)NHCH₂CF₃ 1.018 3,5-Cl₂ C—H C—H C—Me C—H C—Me H CH₂CF₃ 1.0193,5-Cl₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃ 1.020 3,5-(CF₃)₂ C—H C—H C—MeC—H C—Me H CH₂C(O)NHCH₂CF₃ 1.021 3,5-(CF₃)₂ C—H C—H C—Me C—H C—Me HCH₂CF₃ 1.022 3,5-(CF₃)₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃ 1.023 3-Cl,5-CF₃ C—H C—H C—Me C—H C—Me H CH₂C(O)NHCH₂CF₃ 1.024 3-Cl, 5-CF₃ C—H C—HC—Me C—H C—Me H CH₂CF₃ 1.025 3-Cl, 5-CF₃ C—H C—H C—Me C—H C—Me HCH₂CH₂SCH₃

Compounds III-2.001 to III-2.018 Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵R¹⁶ 2.001 3,5-Cl₂ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.002 3,5-Cl₂ C—HC—H N C—H C—H H CH₂CF₃ 2.003 3,5-Cl₂ C—H C—H N C—H C—H H CH₂CH₂SCH₃2.004 3,5-(CF₃)₂ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.005 3,5-(CF₃)₂C—H C—H N C—H C—H H CH₂CF₃ 2.006 3,5-(CF₃)₂ C—H C—H N C—H C—H HCH₂CH₂SCH₃ 2.007 3-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.0083-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂CF₃ 2.009 3-Cl, 5-CF₃ C—H C—H N C—HC—H H CH₂CH₂SCH₃ 2.010 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃2.011 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂CF₃ 2.012 3,5-Cl₂ C—H C—H C—H C—HC—H H CH₂CH₂SCH₃ 2.013 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃2.014 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂CF₃ 2.015 3,5-(CF₃)₂ C—H C—HC—H C—H C—H H CH₂CH₂SCH₃ 2.016 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H HCH₂C(O)NHCH₂CF₃ 2.017 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CF₃ 2.0183-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃

or a pharmaceutically acceptable salt thereof.

#10. The extended release injectable composition according to paragraph#2, wherein isoxazoline active agent is a compound of formula (IVa):

or a pharmaceutically acceptable salt thereof.

#11. The extended release injectable composition according to paragraph#2, wherein isoxazoline compound is a compound of formula (Va):

or a pharmaceutically acceptable salt thereof.

#12. The extended release injectable composition according to paragraph#2, wherein isoxazoline compound is a compound of formula (VIa):

-   -   or a pharmaceutically acceptable salt thereof.

#13. The extended release composition of any one of paragraph #1 toparagraph #12, wherein the pharmaceutically acceptable polymer isselected from the group consisting of polylactides, polyglycolides,polycaprolactones, polyanhydrides, polyamides, polyurethanes,polyesteramides, polyorthoesters, polydioxanones, polyacetals,polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes,polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,polyalkylene succinates, poly(malic acid), poly(amino acids),poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan,copolymers thereof or terpolymers thereof, or combinations or mixturesthereof.

#14. The extended release composition according to paragraph #13,wherein the pharmaceutically acceptable polymer is a copolymer ofpolylactides and polyglycolides.

#15. The extended release composition according to paragraph #13,wherein the pharmaceutically acceptable polymer is a polycaprolactone, apolyamide, a polyanhydride or a polyorthoester.

#16. The extended release injectable composition of any one of paragraph#1 to paragraph #15, wherein the solvent is an alcohol, a liquidpolyethylene glycol, propylene glycol, glycerol, a glycerol ester, acyclic carbonate, 2-pyrrolidone, N-methylpyrrolidone, dimethylisosorbide, dimethylacetamide, glycerol formal, a triglyceride, apropylene glycol diester, a poloxamer, or a mixture of at least two ofthese solvents.

#17. The extended release injectable composition of any one of paragraph#1 to paragraph #15, wherein the solvent is a mixture of awater-miscible solvent and a water-immiscible solvent.

#18. The extended release injectable composition according to paragraph#1 comprising:

-   -   a) about 5 to about 20% (w/w) or about 15 to 30% (w/w) of an        isoxazoline compound of Formula (II):

wherein:

A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from the groupconsisting of CR³ and N, provided that at most 3 of A¹, A², A³, A⁴, A⁵and A⁶ are N;

B¹, B² and B³ are independently selected from the group consisting ofCR² and N;

W is O or S;

R¹ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, each optionally substitutedwith one or more substituents independently selected from R⁶;

each R² is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂;

each R³ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN or —NO₂;

R⁴ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl;

R⁵ is H, OR¹⁰, NR¹¹R¹² or Q¹; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁷; or

R⁴ and R⁵ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂ alkoxy;

each R⁶ is independently halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, —CN or —NO₂;

each R⁷ is independently halogen; C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, C₂-C₇alkylcarbonyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉dialkylaminocarbonyl, C₂-C₇ haloalkylcarbonyl, C₂-C₇ haloalkoxycarbonyl,C₂-C₇ haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl, hydroxy,—NH₂, —CN or —NO₂; or Q²;

each R⁸ is independently halogen, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, C₂-C₄ alkoxycarbonyl, —CN or —NO₂;

each R⁹ is independently halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN, —NO₂, phenyl or pyridinyl;

R¹⁰ is H; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one of more halogen;

R¹¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl;

R¹² is H; Q³; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one or more substituents independentlyselected from R⁷; or

R¹¹ and R¹² are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂and C₁-C₂ alkoxy;

Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9-or 10-membered fused bicyclic ring system optionally containing one tothree heteroatoms selected from up to 1O, up to 1 S and up to 3 N, eachring or ring system optionally substituted with one or more substituentsindependently selected from R⁸;

each Q² is independently a phenyl ring or a 5- or 6-memberedheterocyclic ring, each ring optionally substituted with one or moresubstituents independently selected from R⁹;

Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, each ringoptionally substituted with one or more substituents independentlyselected from R⁹; and

n is 0, 1 or 2 or a pharmaceutically acceptable salt thereof;

b) about 1 to about 30% (w/w) or 1 to about 20% (w/w) of apharmaceutically acceptable polymer which is a polycaprolactone, apolylactide, a polyglycolide or a polylactide and polyglycolidecopolymer;

c) about 40 to about 85% (w/w) of solvent selected from a cycliccarbonate, dimethylisosorbide, a poloxamer, a glycerol ester, atriglyceride, a liquid polyethylene glycol and an alcohol, or a mixturethereof;

d) optionally, about 0.01% to about 2.0% (w/w) of an antioxidant; and

e) optionally about 0.01% to about 5.0% (w/w) of a pharmaceuticallyacceptable additive, excipient or mixtures thereof.

#19. The extended release injectable formulation according to paragraph#18, wherein the compound is a compound of formula (IIc):

or a pharmaceutically acceptable salt thereof.

#20. The extended release injectable formulation according to paragraph#18, wherein the isoxazoline compound is:

-   -   or a pharmaceutically acceptable salt thereof.

#21. The extended release formulation according to any one of paragraph#s 1-20, which further comprise an effective amount at least oneadditional pharmaceutically active agent.

#22. The extended release formulation according to paragraph #21,wherein the additional pharmaceutically active agent is a macrocycliclactone.

#23. The extended release formulation according to paragraph #22,wherein the macrocyclic lactone is abamectin, dimadectin, doramectin,emamectin, eprinomectin, ivermectin, latidectin, lepimectin, selamectin,milbemectin, milbemycin D, milbemycin oxime, moxidectin or nemadectin.

#24. A method for treating or preventing parasites in an animal in needthereof for a period of 3 to 12 months which comprises administering thelong acting injectable formulation according to paragraph #1 to saidanimal.

#25. The method according to paragraph #24 wherein the animal is a dog,cat, sheep or cattle.

#26. The method according to paragraph #24 wherein the parasites aretreated or prevented for about 5 to 6 months.

#27. The method according to paragraph #24 wherein the parasites aretreated or prevented for about 6 months or longer.

#28. The method according to paragraph #24 wherein the parasites arefleas and/or ticks.

#29. The use of an isoxazoline in the preparation of an extended releaseinjectable formulation for the treatment or prevention of a parasiteinfestation or infection on or in an animal.

Having thus described in detail various embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

What is claimed is:
 1. An extended release injectable composition forthe treatment or prevention of parasite infections or infestations in ananimal comprising an antiparasitic effective amount of at least oneisoxazoline active agent, a pharmaceutically acceptable polymer and asolvent or mixture of solvents.
 2. An extended release injectablecomposition for the treatment or prevention of parasite infections orinfestations in an animal comprising an antiparasitic effective amountof at least one isoxazoline active agent, a pharmaceutically acceptablepolymer which is a copolymer of a polylactides and polyglycolides,—asolvent or mixture of solvents, and optionally a surfactant.
 3. Theextended release injectable composition according to claim 2 comprising:a) an antiparasitic effective amount of at least one isoxazoline activeagent, which is: i) an isoxazoline compound of formula (I):

wherein: B¹, B² and B³ are each independently C—R or N; each R isindependently H, halogen, cyano, —NO₂, alkyl, haloalkyl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino oralkoxycarbonyl; R¹ is C₁-C₃alkyl or C₁-C₃haloalkyl; Y is an optionallysubstituted phenylene, naphthylene, indanylene, a 5- or 6-memberedheteroarylene or an 8-10-membered fused heterobicyclylene, wherein theoptional substituents are selected from the group consisting of halogen,alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkylamino, dialkylamino, —CN or —NO₂and NH₂—C(═S)—; Q is X—NR²R³, the group (—CH₂—)(—CH₂—)N—R³, OH, NH₂,alkoxy, haloalkoxy, alkylamino, haloalkylamino, dialkylamino,halodialkylamino, thiol, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, or an optionallysubstituted 5- or 6-membered carbocyclyl, heterocyclyl or heteroarylring; X is (CH₂)_(n), CH(CH₃), CH(CN), C(═O) or C(═S); R² is H, alkyl,alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl,alkylcarbonyl or alkoxycarbonyl; R³ is H, OR⁷, NR⁸R⁹ or Q¹; or alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl,alkylcycloalkyl, cycloalkylalkyl, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, eachoptionally substituted with one or more substituents independentlyselected from R⁴; or R² and R³ are taken together with the nitrogen towhich they are attached to form a ring containing 2 to 6 atoms of carbonand optionally one additional atom selected from the group consisting ofN, S and O, said ring optionally substituted with 1 to 4 substituentsindependently selected from the group consisting of alkyl, halogen, —CN,—NO₂ and alkoxy; each R⁴ is independently halogen; alkyl, cycloalkyl,alkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, alkylamino, haloalkylamino,dialkylamino, dihaloalkylamino, cycloalkylamino, alkylcarbonyl,alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylaminocarbonyl,dihaloalkylaminocarbonyl, hydroxy, —NH₂, —CN or —NO₂; or Q²; each R⁵ isindependently halogen, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,alkylamino, dialkylamino, alkoxycarbonyl, —CN or —NO₂; each R⁶ isindependently halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, alkylamino,dialkylamino, —CN, —NO₂, phenyl or pyridinyl; R⁷ is H; or alkyl,alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachoptionally substituted with one of more halogen; R⁸ is H, alkyl,alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl,alkylcarbonyl or alkoxycarbonyl; R⁹ is H; Q³; or alkyl, alkenyl,alkynyl, cycloalkyl, alkylcycloalkyl or cycloalkylalkyl, each optionallysubstituted with one or more substituents independently selected fromR⁴; or R⁸ and R⁹ are taken together with the nitrogen to which they areattached to form a ring containing 2 to 6 atoms of carbon and optionallyone additional atom selected from the group consisting of N, S and O,said ring optionally substituted with 1 to 4 substituents independentlyselected from the group consisting of alkyl, halogen, —CN, —NO₂ andalkoxy; Q¹ is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an8-, 9- or 10-membered fused bicyclic ring system optionally containingone to three heteroatoms selected from up to 1 O, up to 1 S and up to 3N, each ring or ring system optionally substituted with one or moresubstituents independently selected from R⁵; Q² is independently aphenyl ring or a 5- or 6-membered heterocyclic ring, each ringoptionally substituted with one or more substituents independentlyselected from R⁶; Q³ is a phenyl ring or a 5- or 6-membered heterocyclicring, each ring optionally substituted with one or more substituentsindependently selected from R⁶; and n is 0, 1 or 2; and/or ii) anisoxazoline compound of formula (II):

wherein: A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from thegroup consisting of CR³ and N, provided that at most 3 of A¹, A², A³,A⁴, A⁵ and A⁶ are N; B¹, B² and B³ are independently selected from thegroup consisting of CR² and N; W is O or S; R¹ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁶; each R² is independently H,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, C₂-C₄ alkoxycarbonyl, —CN or —NO₂; eachR³ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN or —NO₂; R⁴ is H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl, C₄-C₇cycloalkylalkyl, C₂-C₇ alkylcarbonyl or C₂-C₇ alkoxycarbonyl; R⁵ is H,OR¹, NR¹¹R¹² or Q¹; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one or more substituents independentlyselected from R⁷; or R⁴ and R⁵ are taken together with the nitrogen towhich they are attached to form a ring containing 2 to 6 atoms of carbonand optionally one additional atom selected from the group consisting ofN, S and O, said ring optionally substituted with 1 to 4 substituentsindependently selected from the group consisting of C₁-C₂ alkyl,halogen, —CN, —NO₂ and C₁-C₂ alkoxy; each R⁶ is independently halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, —CN or —NO₂; each R⁷ is independently halogen; C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylamino, C₂-C₈dialkylamino, C₃-C₆ cycloalkylamino, C₂-C₇ alkylcarbonyl, C₂-C₇alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl,C₂-C₇ haloalkylcarbonyl, C₂-C₇ haloalkoxycarbonyl, C₂-C₇haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl, hydroxy, —NH₂,—CN or —NO₂; or Q²; each R⁸ is independently halogen, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂; each R⁹ is independently halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, —CN, —NO₂,phenyl or pyridinyl; R¹⁰ is H; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one of more halogen;R¹¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl; R¹² is H; Q³; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁷; or R¹¹ and R¹² are takentogether with the nitrogen to which they are attached to form a ringcontaining 2 to 6 atoms of carbon and optionally one additional atomselected from the group consisting of N, S and O, said ring optionallysubstituted with 1 to 4 substituents independently selected from thegroup consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂ and C₁-C₂ alkoxy; Q¹is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or10-membered fused bicyclic ring system optionally containing one tothree heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, eachring or ring system optionally substituted with one or more substituentsindependently selected from R⁸; each Q² is independently a phenyl ringor a 5- or 6-membered heterocyclic ring, each ring optionallysubstituted with one or more substituents independently selected fromR⁹; Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, eachring optionally substituted with one or more substituents independentlyselected from R⁹; and n is 0, 1 or 2; or a pharmaceutically acceptablesalt thereof; and/or iii) an isoxazoline compound of formula (III):

wherein: R₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each which is unsubstituted or substituted with one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; X isaryl or heteroaryl, which may be unsubstituted or substituted by one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; A₁ isoxygen; and A₂ is oxygen, NR₂ or CR₇R₈; G is G-1 or G-2;

B₁, B₂, B₃, B₄ and B₅ are independently N or C—R₉; Y is hydrogen,halogen, —CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, orheterocyclyl or heteroaryl each of which is unsubstituted or substitutedwith one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino,alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—,R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or—NO₂; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11,Y-12 or Y-13;

R₂, R₃ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, R₁₀S(O)—, R₁₀S(O)₂—, R₁₀C(O)—,R₁₀C(S)—, R₁₀R₁₁NC(O)—, R₁₀R₁₁NC(S)—R₁₀OC(O)—; R₄, R₅ and R₆ areindependently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, aryl or heteroaryl; R₇ and R₈ are independently hydrogen,alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl,alkenyl, haloalkenyl, alkynyl or haloalkynyl; R₉ is hydrogen, halogen,—CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachwhich is unsubstituted or substituted with one or more of halogen,hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—,R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; R₁₀, R₁₁, R₁₂ and R₁₃ areeach independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynylor haloalkynyl; or R₁₀ together with R₁₁ form ═O, ═S or ═NR₂; or R₁₂together with R₁₃ form ═O, ═S or ═NR₂; W is O, S or NR₂, n is 1-4; and mis 0, 1 or 2; or a pharmaceutically acceptable salt thereof; and/or iv)an isoxazoline compound of formula (IV)

wherein X¹, X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof; and/oriv) an isoxazoline compound of formula (V)

wherein X¹, X² and X³ are independently H, halogen, C₁-C₃alkyl orC₁-C₃haloalkyl, or a pharmaceutically acceptable salt thereof; and/or v)an isoxazoline compound of formula (VI):

wherein R¹, R² and R³ are independently H, Cl, F or CF₃; Y is thediradical group

T is a C₁-C₆-alkyl group which is unsubstituted or substituted byhalogen, cyano, nitro, amino, hydroxyl, C₁-C₆-alkoxy, C₁-C₆-haloalkoxy,C₁-C₆-alkylthio, C₁-C₆-alkylthio, carboxy, carbamoyl or C₂-C₆-alkanoylgroup which may be unsubstituted or substituted in the alkyl portion byhalogen or a pharmaceutical acceptable salt thereof; and/or vi) anisoxazoline compound of formula (VII):

wherein Y is hydrogen, fluoro, chloro or bromo; R¹ is phenyl substitutedwith 2-4 substituents selected from halogen, methyl, difluoromethyl,trifluoromethyl, methoxy, trifluoromethoxy or trifluoroethoxy; R² ismethyl, fluoromethyl, trifluoromethyl or perfluoroethyl; R^(3a) andR^(3b) are independently selected from hydrogen, methyl, ethyl orfluoromethyl; or R^(3a) and R^(3b) together combine with the carbon towhich they are attached to form a cyclopentyl ring or a cyclohexyl ring;or a pharmaceutically acceptable salt thereof; b) at least onepharmaceutically acceptable polymer; c) at least one solvent or amixture of solvents; d) optionally, an antioxidant; and e) optionally atleast one pharmaceutically acceptable additive, excipient or mixturesthereof.
 4. The extended release injectable composition according toclaim 3, wherein the isoxazoline active agent is a compound of formula(II).
 5. The extended release injectable composition according to claim4, wherein in the isoxazoline active agent is a compound of the formula(IIa):

or a pharmaceutically acceptable salt thereof, wherein: R² independentlyis halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl R⁴ is H or C₁-C₆ alkyl; R⁵ isC₁-C₄ alkyl optionally substituted with one or more R⁷; and R⁷ is C₂-C₇alkylcarbonyl, C₂-C₇ alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉dialkylaminocarbonyl, C₂-C₇ haloalkylcarbonyl, C₂-C₇ haloalkoxycarbonyl,C₂-C₇ haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl; and n is0, 1 or
 2. 6. The extended release injectable composition according toclaim 5, wherein in the isoxazoline active agent is a compound offormula (IIc), (IId), (IIe) or (IIf):

or a pharmaceutically acceptable salt thereof.
 7. The extended releaseinjectable composition according to claim 3, wherein the isoxazolineactive agent is enriched in an enantiomer.
 8. The extended releaseinjectable composition according to claim 7, wherein in the isoxazolineactive agent is a compound of formula (S)-IIc, (S)-IId, (S)-IIe or(S)-IIf:

or a pharmaceutically acceptable salt thereof.
 9. The extended releaseinjectable composition according to claim 3, wherein the isoxazolineactive agent is a compound of formula (III):

wherein: R₁ is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, halocycloalkyl, alkylcycloalkyl orcycloalkylalkyl, each which is unsubstituted or substituted with one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; X isaryl or heteroaryl, which may be unsubstituted or substituted by one ormore of halogen, hydroxy, amino, alkyl- or di(alkyl)amino, alkyl,cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—,R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; A₁ isoxygen; and A₂ is oxygen, NR₂ or CR₇R₈; G is G-1 or G-2;

B₁, B₂, B₃, B₄ and B₅ are independently N or C—R₉; Y is hydrogen,halogen, —CN; or Y is alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, aryl, orheterocyclyl or heteroaryl each of which is unsubstituted or substitutedwith one or more of halogen, hydroxy, amino, alkyl- or di(alkyl)amino,alkyl, cycloalkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, R₇S(O)—,R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—, R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or—NO₂; or Y is Y-1, Y-2, Y-3, Y-4, Y-5, Y-6, Y-7, Y-8, Y-9, Y-10, Y-11,Y-12 or Y-13;

R₂, R₃ are independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, cycloalkyl, R₁₀S(O)—, R₁₀S(O)₂—, R₁₀C(O)—,R₁₀C(S)—, R₁₀R₁₁NC(O)—, R₁₀R₁₁NC(S)—R₁₀OC(O)—; R₄, R₅ and R₆ areindependently hydrogen, alkyl, haloalkyl, thioalkyl, alkylthioalkyl,hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, aryl or heteroaryl; R₇ and R₈ are independently hydrogen,alkyl, haloalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, alkoxyalkyl,alkenyl, haloalkenyl, alkynyl or haloalkynyl; R₉ is hydrogen, halogen,—CN, or alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,cycloalkyl, halocycloalkyl, alkylcycloalkyl or cycloalkylalkyl, eachwhich is unsubstituted or substituted with one or more of halogen,hydroxy, amino, alkyl- or di(alkyl)amino, alkyl, cycloalkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, R₇S(O)—, R₇S(O)₂—, R₇C(O)—, R₇R₈NC(O)—,R₇OC(O)—, R₇C(O)O—, R₇C(O)NR₈—, —CN or —NO₂; R₁₀, R₁₁, R₁₂ and R₁₃ areeach independently hydrogen, alkyl, haloalkyl, thioalkyl,alkylthioalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, haloalkenyl, alkynylor haloalkynyl; or R₁₀ together with R₁₁ form ═O, ═S or ═NR₂; or R₁₂together with R₁₃ form ═O, ═S or ═NR₂; W is O, S or NR₂; n is 1-4; and mis 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
 10. Theextended release injectable composition according to claim 9, whereinisoxazoline agent is a compound of formulae III-1.001 to III-1.025 orIII-2.00-III-2.018:

Compounds III-1.001 to III-1.025 Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵R¹⁶ 1.001 3,5-Cl₂ C—H C—H C—H C—H N H CH₂C(O)NHCH₂CF₃ 1.002 3,5-Cl₂ C—HC—H C—H C—H N H CH₂CF₃ 1.003 3,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂CO₂CH₃1.004 3,5-(CF₃)₂ C—H C—H C—H C—H N CH₃ CH₂CO₂H 1.005 3,5-(CF₃)₂ C—H C—HC—H C—H N CH₃ CH₂C(O)NHCH₂CF₃ 1.006 3,5-(CF₃)₂ C—H C—H C—H C—H N HCH₂C(O)NHCH₂CF₃ 1.007 3,5-(CF₃)₂ C—H C—H C—H C—H N H CH₂CH₂SCH₃ 1.0083,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.009 3,5-(CF₃)₂ C—HC—H C—H C—H C—H H CH₂CH₂SCH₃ 1.010 3,5-(CF₃)₂ C—H C—H C—H C—H C—H HCH₂CF₃ 1.011 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.012 3,5-Cl₂C—H C—H C—H C—H C—H H CH₂CF₃ 1.013 3,5-Cl₂ C—H C—H C—H C—H C—H HCH₂CH₂SCH₃ 1.014 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃ 1.0153-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CF₃ 1.016 3-Cl, 5-CF₃ C—H C—H C—HC—H C—H H CH₂CH₂SCH₃ 1.017 3,5-Cl₂ C—H C—H C—Me C—H C—Me HCH₂C(O)NHCH₂CF₃ 1.018 3,5-Cl₂ C—H C—H C—Me C—H C—Me H CH₂CF₃ 1.0193,5-Cl₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃ 1.020 3,5-(CF₃)₂ C—H C—H C—MeC—H C—Me H CH₂C(O)NHCH₂CF₃ 1.021 3,5-(CF₃)₂ C—H C—H C—Me C—H C—Me HCH₂CF₃ 1.022 3,5-(CF₃)₂ C—H C—H C—Me C—H C—Me H CH₂CH₂SCH₃ 1.023 3-Cl,5-CF₃ C—H C—H C—Me C—H C—Me H CH₂C(O)NHCH₂CF₃ 1.024 3-Cl, 5-CF₃ C—H C—HC—Me C—H C—Me H CH₂CF₃ 1.025 3-Cl, 5-CF₃ C—H C—H C—Me C—H C—Me HCH₂CH₂SCH₃

Compounds III-2.001 to III-2.018 Compound No. (Z)_(p) B⁵ B⁴ B³ B² B¹ R¹⁵R¹⁶ 2.001 3,5-Cl₂ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.002 3,5-Cl₂ C—HC—H N C—H C—H H CH₂CF₃ 2.003 3,5-Cl₂ C—H C—H N C—H C—H H CH₂CH₂SCH₃2.004 3,5-(CF₃)₂ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.005 3,5-(CF₃)₂C—H C—H N C—H C—H H CH₂CF₃ 2.006 3,5-(CF₃)₂ C—H C—H N C—H C—H HCH₂CH₂SCH₃ 2.007 3-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂C(O)NHCH₂CF₃ 2.0083-Cl, 5-CF₃ C—H C—H N C—H C—H H CH₂CF₃ 2.009 3-Cl, 5-CF₃ C—H C—H N C—HC—H H CH₂CH₂SCH₃ 2.010 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃2.011 3,5-Cl₂ C—H C—H C—H C—H C—H H CH₂CF₃ 2.012 3,5-Cl₂ C—H C—H C—H C—HC—H H CH₂CH₂SCH₃ 2.013 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂C(O)NHCH₂CF₃2.014 3,5-(CF₃)₂ C—H C—H C—H C—H C—H H CH₂CF₃ 2.015 3,5-(CF₃)₂ C—H C—HC—H C—H C—H H CH₂CH₂SCH₃ 2.016 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H HCH₂C(O)NHCH₂CF₃ 2.017 3-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CF₃ 2.0183-Cl, 5-CF₃ C—H C—H C—H C—H C—H H CH₂CH₂SCH₃

or a pharmaceutically acceptable salt thereof.
 11. The extended releaseinjectable composition according to claim 3, wherein isoxazoline activeagent is a compound of formula (IVa):

or a pharmaceutically acceptable salt thereof.
 12. The extended releaseinjectable composition according to claim 3, wherein isoxazolinecompound is a compound of formula (Va):

or a pharmaceutically acceptable salt thereof.
 13. The extended releaseinjectable composition according to claim 3, wherein isoxazolinecompound is a compound of formula (VIa):

or a pharmaceutically acceptable salt thereof.
 14. The extended releasecomposition according to claim 1, wherein the pharmaceuticallyacceptable polymer is selected from the group consisting ofpolylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyesteramides, polyorthoesters,polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates,poly(malic acid), poly(amino acids), poly(methyl vinyl ether),poly(maleic anhydride), chitin, chitosan, copolymers thereof orterpolymers thereof, or combinations or mixtures thereof.
 15. Theextended release injectable composition according to claim 2, whereinthe solvent is an alcohol, a liquid polyethylene glycol, propyleneglycol, glycerol, a glycerol ester, a cyclic carbonate, 2-pyrrolidone,N-methylpyrrolidone, dimethyl isosorbide, dimethylacetamide, glycerolformal, a triglyceride, a propylene glycol diester, a poloxamer, or amixture of at least two of these solvents.
 16. The extended releaseinjectable composition according to claim 2, wherein the solvent is amixture of a water-miscible solvent and a water-immiscible solvent. 17.The extended release injectable composition according to claim 2comprising: a) about 5 to 20% (w/w) of an isoxazoline compound ofFormula (II):

wherein: A¹, A², A³, A⁴, A⁵ and A⁶ are independently selected from thegroup consisting of CR³ and N, provided that at most 3 of A¹, A², A³,A⁴, A⁵ and A⁶ are N; B¹, B² and B³ are independently selected from thegroup consisting of CR² and N; W is O or S; R¹ is C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁶; each R² is independently H,halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy,C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, C₂-C₄ alkoxycarbonyl, —CN or —NO₂; eachR³ is independently H, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₆cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ haloalkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ haloalkylsulfonyl, C₁-C₆alkylamino, C₂-C₆ dialkylamino, —CN or —NO₂; R⁴ is H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl, C₄-C₇cycloalkylalkyl, C₂-C₇ alkylcarbonyl or C₂-C₇ alkoxycarbonyl; R⁵ is H,OR¹, NR¹¹R¹² or Q¹; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇ cycloalkylalkyl, eachoptionally substituted with one or more substituents independentlyselected from R⁷; or R⁴ and R⁵ are taken together with the nitrogen towhich they are attached to form a ring containing 2 to 6 atoms of carbonand optionally one additional atom selected from the group consisting ofN, S and O, said ring optionally substituted with 1 to 4 substituentsindependently selected from the group consisting of C₁-C₂ alkyl,halogen, —CN, —NO₂ and C₁-C₂ alkoxy; each R⁶ is independently halogen,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆alkylsulfonyl, —CN or —NO₂; each R⁷ is independently halogen; C₁-C₆alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆ alkylamino, C₂-C₈dialkylamino, C₃-C₆ cycloalkylamino, C₂-C₇ alkylcarbonyl, C₂-C₇alkoxycarbonyl, C₂-C₇ alkylaminocarbonyl, C₃-C₉ dialkylaminocarbonyl,C₂-C₇ haloalkylcarbonyl, C₂-C₇ haloalkoxycarbonyl, C₂-C₇haloalkylaminocarbonyl, C₃-C₉ dihaloalkylaminocarbonyl, hydroxy, —NH₂,—CN or —NO₂; or Q²; each R⁸ is independently halogen, C₁-C₆ alkoxy,C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₂-C₄alkoxycarbonyl, —CN or —NO₂; each R⁹ is independently halogen, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₃-C₆ cycloalkyl, C₃-C₆ halocycloalkyl, C₁-C₆alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ haloalkylthio, C₁-C₆alkylsulfinyl, C₁-C₆ haloalkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆haloalkylsulfonyl, C₁-C₆ alkylamino, C₂-C₆ dialkylamino, —CN, —NO₂,phenyl or pyridinyl; R¹⁰ is H; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one of more halogen;R¹¹ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ alkylcycloalkyl, C₄-C₇ cycloalkylalkyl, C₂-C₇ alkylcarbonyl orC₂-C₇ alkoxycarbonyl; R¹² is H; Q³; or C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ alkylcycloalkyl or C₄-C₇cycloalkylalkyl, each optionally substituted with one or moresubstituents independently selected from R⁷; or R¹¹ and R¹² are takentogether with the nitrogen to which they are attached to form a ringcontaining 2 to 6 atoms of carbon and optionally one additional atomselected from the group consisting of N, S and O, said ring optionallysubstituted with 1 to 4 substituents independently selected from thegroup consisting of C₁-C₂ alkyl, halogen, —CN, —NO₂ and C₁-C₂ alkoxy; Q¹is a phenyl ring, a 5- or 6-membered heterocyclic ring, or an 8-, 9- or10-membered fused bicyclic ring system optionally containing one tothree heteroatoms selected from up to 1 O, up to 1 S and up to 3 N, eachring or ring system optionally substituted with one or more substituentsindependently selected from R⁸; each Q² is independently a phenyl ringor a 5- or 6-membered heterocyclic ring, each ring optionallysubstituted with one or more substituents independently selected fromR⁹; Q³ is a phenyl ring or a 5- or 6-membered heterocyclic ring, eachring optionally substituted with one or more substituents independentlyselected from R⁹; and n is 0, 1 or 2 or a pharmaceutically acceptablesalt thereof; b) about 1 to about 30% (w/w) of a pharmaceuticallyacceptable polymer which is a copolymer of polylactides andpolyglycolides that has a lactide to glycolide ratio of 40:60 to85:15(weight:weight); c) about 40 to about 85% (w/w) of solvent selectedfrom a cyclic carbonate, dimethylisosorbide, a poloxamer, a glycerolester, a triglyceride, a liquid polyethylene glycol and an alcohol, or amixture thereof; d) optionally, about 0.01% to about 2.0% (w/w) of anantioxidant; e) optionally, about 0.1% to about 10% (w/w) of asurfactant and f) optionally about 0.01% to about 5.0% (w/w) of apharmaceutically acceptable additive, excipient or mixtures thereof. 18.The extended release injectable formulation according to claim 17,wherein the compound is a compound of formula (IIc):

or a pharmaceutically acceptable salt thereof.
 19. The extended releaseinjectable formulation according to claim 17, wherein the isoxazolinecompound is:

or a pharmaceutically acceptable salt thereof.
 20. The extended releaseformulation according to claim 17, wherein the solvent is a cycliccarbonate.
 21. The extended release formulation according to claim 17,wherein the solvent is a solvent mixture comprising a cyclic carbonateand a glycerol ester.
 22. The extended release formulation according toclaim 18, wherein the ratio of cyclic carbonate to glycerol ester isabout 1.5:1 to about 15:1 (w/w).
 23. The extended release formulationaccording to claim 17 or 18, wherein the cyclic carbonate is propylenecarbonate.
 24. The extended release formulation of claim 17 or 18,wherein the glycerol ester is triacetin.
 25. The extended releaseformulation of claim 17 or claim 18, wherein the solvent is a mixturecomprising propylene carbonate and triacetin.
 26. The extended releaseformulation according to claim 21 wherein the solvent mixture furthercomprises a poloxamer.
 27. The extended release formulation according toclaim 26, which comprises about 0.5 to about 20% (w/w) of the poloxamer.28. The extended release formulation according to claim 17, wherein theratio of the copolymer of polylactides and polyglycolides to theisoxazoline compound of Formula (II) is about 1.5:1 to about 1:1.5(weight:weight).
 29. The extended release formulation according to claim28, wherein the weight average molecular weight of the copolymer ofpolylactides and polyglycolides is from about 5 to about 20 kDa.
 30. Theextended release formulation according to claim 2, which furthercomprise an effective amount at least one additional pharmaceuticallyactive agent.
 31. The extended release formulation according to claim30, wherein the additional pharmaceutically active agent is amacrocyclic lactone.
 32. The extended release formulation according toclaim 31, wherein the macrocyclic lactone is abamectin, dimadectin,doramectin, emamectin, eprinomectin, ivermectin, latidectin, lepimectin,selamectin, milbemectin, milbemycin D, milbemycin oxime, moxidectin ornemadectin.
 33. A method for treating or preventing parasites in ananimal in need thereof for a period of 3 to 12 months which comprisesadministering the long acting injectable formulation according to claim2 to said animal.
 34. The method according to claim 33 wherein theanimal is a dog, cat, sheep or cattle.
 35. The method according to claim33 wherein the parasites are treated or prevented for about 5 to 6months.
 36. The method according to claim 33 wherein the parasites aretreated or prevented for about 6 months or longer.
 37. The methodaccording to claim 33 wherein the parasites are fleas and/or ticks. 38.The use of an isoxazoline in the preparation of an extended releaseinjectable formulation for the treatment or prevention of a parasiteinfestation or infection on or in an animal.